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Nisar, Samia. "Role of ATP2B4 and human malaria : looking for functional genetic variants associated with malaria." Thesis, Aix-Marseille, 2020. http://theses.univ-amu.fr.lama.univ-amu.fr/200911_NISAR_992dobfs271wcdsgy656twqjfn399ockic_TH.pdf.
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GWAS pour le paludisme grave identifié 30 variantes génétiques situées dans régions non codantes, avec seulement quelques associations répliquées dans des populations indépendantes. Dans cette étude, nous avons cherché à identifier les variantes génétiques potentielles situées dans ces loci et à démontrer leur activité fonctionnelle. Nous avons systématiquement étudié l'effet régulateur des SNP en déséquilibre liaison avec les tagSNPs associés au paludisme sévère dans plusieurs populations. L'annotation et priorisation ont conduit à l'identification d'une région régulatrice contenant 5 SNP ATP2B4 en déséquilibre liaison avec le tagSNP. Nous confirmé l'association de rs10900585 et trouvé des associations significatives de paludisme sévère avec nos candidats dans population sénégalaise. Nous montré que cette région avait à la fois une activité promoteur et un activateur et que l'individu et combinaison de SNP avaient un effet en utilisant des dosages de luciférase. En outre, la délétion médiée par CRISPR / Cas9 de cette région a diminué le transcrit ATP2B4 et les niveaux de protéines et a augmenté la concentration intracellulaire de Ca2+ dans les cellules K562. Ensemble, nos données montrent les variantes génétiques associées au paludisme grave modifient l'activité d'un promoteur avec une fonction d'activateur. Nous montré que cet amplificateur contrôle l'expression de l'ATP2B4 qui code l'ATPase 4 (PMCA4) transportant le calcium dans la membrane plasmique, qui est la principale pompe à calcium des globules rouges. La modification de l'activité de cet Epromoter affecte le risque de paludisme sévère probablement par l'effet de la concentration de calcium sur la parasitémieGenome-wide association studies (GWAS) for severe malaria have identified 30 genetic variants mostly located in non-coding regions, with only few associations replicated in independent populations. In this study, we aimed at identifying potential causal genetic variants located in these loci and demonstrate their functional activity. We systematically investigated the regulatory effect of the SNPs in linkage disequilibrium with the tagSNPs associated with severe malaria in several populations. Annotating and prioritizing genetic variants led to the identification of a regulatory region containing 5 ATP2B4 SNPs in linkage disequilibrium with the tagSNP rs10900585. We confirmed the association of rs10900585 and also found significant associations of severe malaria with our candidate SNPs (rs11240734, rs1541252, rs1541253, rs1541254, and rs1541255) in a Senegalese population. Then, we showed that this region had both a promoter and an enhancer activity and that both individual SNPs and the combination of SNPs had an effect using luciferase reporter assays. In addition, CRISPR/Cas9-mediated deletion of this region decreased ATP2B4 transcript and protein levels and increased Ca2+ intracellular concentration in K562 cell line. Taken together, our data show that severe malaria associated genetic variants alters the activity of a promoter with enhancer function. We showed that this enhancer controls the expression of ATP2B4 that encodes plasma membrane calcium-transporting ATPase 4 (PMCA4), which is the major calcium pump on red blood cells. Altering the activity of this Epromoter affects the risk of severe malaria probably through calcium concentration effect on parasitaemia
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Tétard, Marilou. "Mechanisms associated to hemoglobinopathic protection against plasmodium falciparum malaria." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCC257.
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La protection contre le paludisme, conférée par les hémoglobinopathies (HbS et HbC), a été bien définie mais les mécanismes moléculaires et cellulaires sous-jacents restent méconnus. Un des mécanismes proposés, implique une présentation anormale des PfEMP1 à la surface des globules rouges infectés et a été associé à une diminution de l’expression de surface de ces PfEMP1 causant une diminution de l’adhérence des globules rouges parasités (GRp) aux cellules de l’endothélium vasculaire. Dans une étude de cohorte de femmes enceintes au Bénin, nous avons premièrement montré que le génotype HbAC et non HbAS était associé à un poids de naissance plus élevé des nouveau-nés parmi les femmes ayant souffert de paludisme gestationnel. PfEMP1-VAR2CSA est le ligand parasitaire principal interagissant avec la CSA placentaire et joue donc un rôle primordial dans le paludisme gestationnel. Nous avons étudié la capacité de parasites exprimant VAR2CSA et cultivés dans des globules rouges HbAS et HbAC à adhérer à la CSA.Bien que nous ayons observé une diminution de l’adhérence pour les GRp HbAS et HbAC en comparaison aux GRp HbAA, nous n’avons observé aucune différence d’expression de surface de VAR2CSA. Cela pourrait suggérer que VAR2CSA est moins fonctionnel dans les globules rouges de patients porteurs d’hémoglobinopathies. Nous avons ensuite initié une étude de transcriptome différentiel durant la croissance asexuée du parasite en globule rouge HbAA, HbAS et HbAC. Bien que très peu de gènes aient été trouvés différentiellement exprimés entre les parasites HbAA et les parasites HbAC, l’expression d’un grand nombre de gènes s’avère différente entre les parasites HbAS et HbAAMalaria protection conferred by hemoglobinopathies (HbS or HbC hemoglobin polymorphisms) is well established, but the underlying molecular and cellular mechanisms remain largely unknown. One proposed protective mechanism involves the abnormal display of PfEMP1 on the surface of infected erythrocytes (IEs), and has been associated with reduced surface levels of PfEMP1 and knob density, in turn leading to decreased IEs binding to endothelial receptors.Adhesion of IEs to placental chondroitin sulfate A (CSA) is a central pathological process in placental (PM) malaria, predominantly operated by the VAR2CSA-PfEMP1. In a cohort study on pregnant women from Benin, we reported that HbAC but not HbAS maternal genotype is associated with higher new-born birthweight among women with PM. We examined the ability of VAR2CSA-expressing IEs grown in HbAS and HbAC erythrocytes to cytoadhere to CSA and assessed VAR2CSA surface expression. Although we observed a significant decrease of cytoadhesion, VAR2CSA surface expression was unchanged in the HbAS and HbAC erythrocytes. This suggested that VAR2CSA might be less functional in IEs derived from patients with hemoglobinopathies. We further initiated a differential transcriptomic analysis during asexual growth (10, 20, 30 and 40 h post-invasion) using high-throughput RNA sequencing of NF54 parasites expressing VAR2CSA grown in HbAA, HbAS or HbAC erythrocytes. Although, few genes were differentially transcribed between parasites grown in HbAA and HbAC red cells, a high number of genes were differentially transcribed between parasites grown in HbAA and HbAS. Overall, our study provides an important stepping-stone towards the understanding of protective mechanisms associated with hemoglobinopathies
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Lindh, Jenny. "Identification of bacteria associated with malaria mosquitoes - Their characterisation and potential use." Doctoral thesis, Stockholm : Department of Genetics, Microbiology and Toxicology, Stockholm University, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-6685.
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Silva, Leandro Gustavo da. "Papel dos receptores do tipo Toll (TLRs) na imunopatogênese da malária associada à gravidez." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/42/42135/tde-21032012-160144/.
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A malária asociada à gavidez pode gerar complicações para a mãe e para o feto. Receptores do tipo Toll (TLR) TLR2, TLR4 e TLR9, podem reconhecer componentes do Plasmódio. Estes receptores sinalizam via proteína MyD88. Contudo existem poucos dados sobre os TLR na malária placentária. Assim, o objetivo desse trabalho foi estudar o papel dos TLR2, 4, 9 e da MyD88 na malária placentária. Dentre fêmeas C57BL/6, TLR2-/-, TLR9-/- e MyD88-/-, a linhagem MyD88-/- apresentou maiores níveis de parasitemia, sobrevivência e cuidado parental, e ainda placentas de fêmeas MyD88-/- infectadas, ao contrario das TLR2-/- e TLR9-/-, não tiveram diminuição do espaço vascular em relação aos controles. Animais C57BL/6 infectados apresentaram aumento do mRNA de IL1-b e IL-6 na placenta, o que não ocorreu nos MyD88-/-. Gestantes C57BL/6 e MyD88-/- infectadas tiveram mais esplenócitos, com expansão preferencial de linfócitos B (CD19+). Também foi evidenciado nos animais C57BL/6 infectados um aumento da expressão do marcador de ativação CD69 nos linfócitos TCD8+. Em conjunto, estes resultados sugerem que a sinalização via MyD88 é importante para o desenvolvimento da malária placentaria e esta pode estar relacionada com a resposta inflamatória exacerbada induzida pelo parasita.Pregnancy associated malaria can lead to complications both for the mother and the fetus. Toll like receptors (TLR) TLR2, TLR4 and TLR9 can recognize components of the Plasmodium sp. These receptors signal through the MyD88 protein. However there are few data on TLR in placental malaria. Thus, The objective of this work was to study the role of TLR2, 4, 9 and MyD88 in placental malaria. Among female mice C57BL/6, TLR2-/-, TLR9-/- and MyD88-/-, the lineage MyD88-/- showed higher levels of parasitemia, survival and parental care, and still placentas of MyD88-/- infected female, differently of TLR2-/- and TLR9-/-, had no decrease in the vascular space compared to controls. Animals C57BL/6 infected showed increased mRNA for IL1-b and IL-6 in the placenta, which did not occur in MyD88-/-. Pregnant infected C57BL/6 and MyD88-/- had more splenocytes, with preferential expansion of B lymphocytes (CD19+). in infected C57BL/6 was also demonstrated an increased expression of the activation marker CD69 on CD8+ T lymphocytes. Together, these results suggest that signaling through MyD88 is important for the development of placental malaria and this may be related with an increased inflammatory response induced by the parasite.
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Loucoubar, Cheikh. "Statistical genetic analysis of infectious disease (malaria) phenotypes from a longitudinal study in a population with significant familial relationships." Phd thesis, Université René Descartes - Paris V, 2012. http://tel.archives-ouvertes.fr/tel-00685104.
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Long term longitudinal surveys have the advantage to enable several sampling of the studied phenomena and then, with the repeated measures obtained, find a confirmed tendency. However, these long term surveys generate large epidemiological datasets including more sources of noise than normal datasets (e.g. one single measure per observation unit) and potential correlation in the measured values. Here, we studied data from a long-term epidemiological and genetic survey of malaria disease in two family-based cohorts in Senegal, followed for 19 years (1990-2008) in Dielmo and for 16 years (1993-2008) in Ndiop. The main objectives of this work were to take into account familial relationships, repeated measures as well as effect of covariates to measure both environmental and host genetic (heritability) impacts on the outcome of infection with the malaria parasite Plasmodium falciparum, and then use findings from such analyses for linkage and association studies. The outcome of interest was the occurrence of a P. falciparum malaria attack during each trimester (PFA). The two villages were studied independently; epidemiological analyses, estimation of heritability and individual effects were then performed in each village separately. Linkage and association analyses used family-based methods (based on the original Transmission Disequilibrium Test) known to be immune from population stratification problems. Then to increase sample size for linkage and association analyses, data from the two villages were used together.
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Redmond, Seth. "Population structure and genome-wide association in the malaria vectors Anopheles gambiae and Anopheles coluzzii." Thesis, Paris 6, 2015. http://www.theses.fr/2015PA066085/document.
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Malgré le succès des insecticides pour le contrôle du paludisme, la transmission continue dans la plupart des pays d’Afrique sub-saharienne. La recherche pour de nouveaux moyens de contrôle (plus spécialement la modification génétique des populations vecteurs), ou l'utilisation plus efficace des contrôles actuels, vont nécessiter une recherche sur les structures de populations de moustiques et les processus d’immunisation qui importent pour la transmission du Plasmodium chez les moustiques sauvages. Par ailleurs, l’utilisation des techniques d’association génomique ‘GWAS’ est basée sur un réelle compréhension des structures des populations.Ma thèse inclura une description detaillée du système immunitaire du moustique, basée sur la recherche actuelle et des comparaisons génomiques; ainsi que des descriptions des principales voies immunitaires, et des gênes potentiels mal-caracterisés qui peuvent être trouvés dans une étude GWAS. Ainsi qu’une description des connaissances actuelles des structures des populations, dont la speciation du gambiae / coluzzii, et les effets des grandes variations structurelles.Je présenterai le développement d’un nouveau moyen d'identification des variations structurelles ; utilisant les techniques d’ “apprentissage automatique” permettant d'identifier les karyotypes directement à partir des séquences haut-débit, menant à des résultats d’une précision sans précédent.Je présenterai également la première vraie cartographie génomique du ‘tout-génome’ du moustique. Les colonies sont fondées par des moustiques sauvages; les fondateurs sont controlées par strates, incluant également des sous-espèces et variations structurelles majeures. Avec ces colonies une méthode innovant de cartographie est utilisée: dans un premier temps, une identification des grandes régions au sein des groupes phenotypées par la perte de hétérogénéité; puis dans un second temps, le génotypage individuel ‘Sequenom’ sera utilisé pour une cartographie exacte. Cette méthode est utilisée pour l’identification d’une région avec un effet phenotypique sur la prévalence des infections dans la nature.Enfin, je suggèrerai comment ces techniques peuvent être importantes à l’avenir pour l’application du contrôle génomique dans la natureDespite successes in the use of insecticides in the control of malaria, malaria transmission continues in much of sub-saharan Africa. The search for novel methods of control (in particular genetic modification of vector populations), or of superior implementation of the currently available methods will require both greater knowledge of the population structure of the mosquito, and of the immune processes that are important in the wild. It is important to note that the mapping of novel immune genes, via genome wide association studies (GWAS) is predicated on a firm understanding of the population structure.My thesis will include a detailed description of the mosquito innate immune system based on current research and comparative genomics; this will illustrate the major pathways that might be employed in the anti-malarial response, and some potential uncharacterised genes that might be implicated in any GWAS study. It will also include a summary of what is known about the mosquito’s population structure, in particular the gambiae / coluzzii speciation event and the implication of chromosomal inversions in the speciation process.I will present the development of a novel approach to the identification of chromosomal inversions; using machine-learning techniques in order to call inversion karyotypes directly from sequence, leading to calls of unprecedented accuracy.I will also present the first truly genome-wide association study to have been performed in the mosquito. Strata-controlled populations of mosquitoes were derived from the wild, including restriction on the basis of subspecies and chromosomal inversion. A two-stage mapping design was then devised in which loss-of-heterozygosity is used to identify broad regions in phenotype pools, before fine-resolution mapping by Sequenom genotyping in individuals. This was used to identify a novel locus with a phenotypic effect on infection prevalence.Finally I will describe how these techniques and findings could be important in the future application of genetic control in the wild
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Thomas, Phaedra J. "A Forward Genetic Screen Identifies Factors Associated with Fever Pathogenesis in Plasmodium falciparum." Scholar Commons, 2015. http://scholarcommons.usf.edu/etd/5785.
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Infectious diseases that spread from person-to-person and continent-to-continent are a cause for concern for any health entity. One such disease is malaria, a mosquito-borne infection instigated by the protozoan parasite, Plasmodium falciparum. Hundreds of millions of people are affected annually and it is responsible for nearly 1 million deaths. It is the most fatal species causing malaria and proliferates in human red blood cells with a life cycle occurring every 48 hours. At this time, the parasite’s late stage form or schizont bursts from the erythrocyte releasing immune-inducing particles and infective forms (merozoites) into the bloodstream. The merozoites go on to infect other red blood cells as human immunity leads to fever. Fever is a hallmark symptom of malaria and effectively inhibits the growth of late stage parasites. Plasmodium still manages to complete its life cycle as early stages or rings are not affected by febrile temperatures. It is this facet of parasite biology that prompts our research into identifying genetic factors associated with fever.
The parasite’s response under elevated body temperature may offer further insight into its adaptive mechanism. A heat shock assay was developed in order to simulate fever in vitro. Mutant parasite cultures were subjected to 41°C for 8 hours and returned to normal body temperature or 37°C for the remainder of the life cycle. The piggyBac mutagenesis system allows for the evaluation of phenotypes associated with a particular genotype as the transposon inserts randomly into the gene. This often leads to changes in function that may cause delays in invasion or attenuation of growth. Determining the genes responsible for these phenotypes would be a great advantage to the field of drug discovery.
Collaborative efforts to develop vaccines and new antimalarial drugs are underway as resistance to current methods of treatment is on the rise. Such circumstances require new technologies for detecting novel drug targets or pathways in the parasite that can be significantly affected by these therapeutics. QISeq is a next generation sequencing tool that identifies genes with a particular phenotype that may alter intraerythrocytic development of P. falciparum. This technique was utilized in our study to confirm the heat shock phenotype with a high-throughput approach. The genomic DNA of pooled parasite cultures was sequenced to reveal those mutants sensitive and/or resistant to febrile temperature exposure. Through bioinformatics analyses, functional associations between genes can be made that lead to biological pathways of interest for therapeutic research.
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Prapansilp, Panote. "Molecular pathological investigation of the pathophysiology of fatal malaria." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:e966a2f2-a37d-4586-b09e-2bb616e5dce2.
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Malaria remains one of the world's major health problems, especially in developing countries. A better understanding of the pathology and pathophysiology of severe malaria is key to develop new treatments. Different approaches have been used in malaria research including the in vitro co-culture models with endothelial cells and both murine and simian animal models. However these are open to controversy due to disagreement on their representativeness of human disease. Using human post-mortem tissue in malaria research is another important approach but is practically challenging, limiting the availability of post mortem samples from malaria patients. The work in this thesis had two main themes. First I examined the role of the endothelial signalling Angiopoetin-Tie-2 receptor pathway in malaria. Ang-2 has been shown to be a significant biomarker of severe and fatal malaria. I examined the tissue specific expression of proteins from this pathway in post-mortem brain tissues from fatal malaria cases, but found no difference between cerebral malaria and non-cerebral malaria cases. Ang-2 correlated with the severity of malaria in these patients. An attempt to examine the interaction of hypoxia and the Ang-Tie-2 pathway in vitro using a co-culture model of human brain endothelial cells was unsuccessful due to contamination of the cell line. The second part of the thesis aimed to utilise molecular pathology techniques including miRNA and whole-genome microarrays. I have shown for the first time that these can be successfully applied to human post-mortem tissue in malaria. First I used archival tissues to examine the microRNA signature in the kidney of patients with malaria associated renal failure. Second I optimised a protocol to preserve post mortem tissue for molecular pathology, from an autopsy study in Mozambique. Using the subsequent total mRNA transcriptomic data and bioinformatics analysis this work has expanded our knowledge of differential gene expression and the families of genes which are dysregulated in the brain in response to malaria infection.
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Fernandez-Reyes, Delmiro. "Association of polymorphisms in intercellular adhesion molecule-1 (ICAM-1) with severe disease in Plasmodium falciparum malaria." Thesis, University of Oxford, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299524.
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MACHADO, Patrícia Isabel Pires. "Pyruvate kinase and glucose-6-phosphate dehydrogenase deficies and their association with malaria - population genetics and proteomic studies." Doctoral thesis, Instituto de Higiene e Medicina Tropical, 2013. http://hdl.handle.net/10362/11346.
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A malária é reconhecida como uma das principais forças selectivas a actuar na história recente no genoma humano. Inúmeros polimorfismos genéticos têm sido descritos como protectores contra a gravidade da malária, como o alelo HbS (designado de traço falciforme) e o alelo G6PD A- (associado à deficiência de G6PD). Mais recentemente, também a deficiência de PK foi associada com a protecção contra a malária. Evidências desta associação foram obtidas em estudos com modelos de roedor e estudos in vitro utilizando GV humanos deficientes em PK. Até à data, não foram obtidos dados em populações humanas que revelem esta associação: ainda não foi identificada uma variante de PK com uma prevalência elevada em regiões endémicas de malária e não foram identificadas marcas de selecção na região do gene que codifica para a PK (gene PKLR). Além disso, os mecanismos subjacentes à protecção contra a malária por deficiências enzimáticas dos GV não estão bem esclarecidos.
Assim, os objectivos do presente estudo foram: investigar os polimorfismos genéticos humanos com associação com a malária em Cabo Verde; pesquisar marcas de selecção da malária na região do gene PKLR em populações Africanas; determinar a frequência da deficiência em PK e identificar uma eventual variante da enzima que possa estar sob
selecção positiva em regiões endémicas de malária; avaliar o efeito das duas deficiências enzimáticas (PK e G6PD) na invasão e maturação do parasita em culturas in vitro de Plasmodium usando GV normais e deficientes; e analisar o perfil proteómico de GV infectados e não infectados, normais e com deficiência (em PK e G6PD), bem como de parasitas isolados de GV tanto deficientes como normais.
Em Cabo Verde (área epidémica), não foram identificadas marcas de selecção pela malária, através da análise dos vários polimorfismos. No entanto, quando a análise foi realizada em dois países endémicos (Angola e Moçambique), foram detectadas várias marcas de selecção: a genotipagem de microssatélites (STRs) e polimorfismos de base
única (SNPs) localizados na vizinhança do gene PKLR revelou uma diferenciação consideravelmente maior entre as populações Africana e Europeia (Portuguesa), do que a diferenciação determinada aquando da utilização de marcadores genéticos neutros.
Além disso, uma região genómica de maior amplitude apresentou um Desequilíbrio de Ligação (LD) significativo no grupo de malária não grave (e não no grupo de malária grave), sugerindo que a malária poderá estar a exercer pressão selectiva sobre a região do genoma humano que envolve o gene PKLR.
No estudo que incidiu na determinação da prevalência da deficiência de PK no continente Africano (realizado em Moçambique), esta revelou-se elevada - 4,1% - sendo o valor mais elevado descrito até ao momento a nível mundial para esta enzimopatia. Na pesquisa de mutações que pudessem estar na causa deste fenótipo (baixa actividade de PK), foi identificada uma mutação não sinónima 829G>A (277Glu>Lys),
significativamente associada à baixa actividade enzimática. Esta mutação foi também identificada em Angola, São Tomé e Príncipe e Guiné Equatorial, onde a frequência de portadores heterozigóticos foi entre 2,6 e 6,7% (valores que se encontram entre os mais elevados descritos globalmente para mutações associadas à deficiência em PK). Não foi
possível concluir acerca da associação entre a deficiência de PK e o grau de severidade da malária e da associação entre o alelo 829A e a mesma, devido ao baixo número de amostras.
Os resultados dos ensaios de invasão/maturação do parasita sugeriram que, nos GV com deficiência de PK ou G6PD, a invasão (onde está envolvida a membrana do GV hospedeiro e o complexo apical do parasita) é mais relevante para a eventual protecção contra a malária do que a maturação. Os resultados da análise proteómica revelaram respostas diferentes por parte do parasita nas duas condições de crescimento (GV com deficiência de PK e GV com deficiência de G6PD). Esta resposta parece ser proporcional à gravidade da deficiência enzimática. Nos parasitas que cresceram em GV deficientes em G6PD (provenientes de um indivíduo assintomático), a principal alteração observada (relativamente às condições normais) foi o aumento do número de
proteínas de choque térmico e chaperones, mostrando que os parasitas responderam às condições de stress oxidativo, aumentando a expressão de moléculas de protecção. Nos parasitas que cresceram em condições de deficit de PK (GV de indivíduo com crises hemolíticas regulares, dependente de transfusões sanguíneas), houve alteração da expressão de um maior número de proteínas (relativamente ao observado em condições normais), em que a maioria apresentou uma repressão da expressão. Os processos biológicos mais representados nesta resposta do parasita foram a digestão da hemoglobina e a troca de proteínas entre hospedeiro e parasita/remodelação da superfície do GV. Além disso, uma elevada percentagem destas proteínas com expressão alterada está relacionada com as fendas de Maurer, que desempenham um papel importante na patologia da infecção malárica. É colocada a hipótese de que a protecção contra a malária em GV deficientes em PK está relacionada com o processo de remodelação da membrana dos GV pelo parasita, o que pode condicionar a invasão por novos parasitas e a própria virulência da malária. Os resultados da análise do proteoma dos GV contribuirão para confirmar esta hipótese.Malaria has been recognized as the strongest known force for evolutionary selection in the recent history of the human genome. Several human genetic polymorphisms have been described as protective against malaria severity, as the HbS allele (sickle cell trait) and G6PD A- allele (causing G6PD deficiency). More recently, PK deficiency has also been described as protective against malaria. Evidences were obtained in murine models and in vitro studies using PK-deficient human RBC. Human population data has not been obtained so far: a high prevalent PK variant has yet to be identified in malaria endemic regions and selection signatures in the genome region around RBC PKencoding gene (PKLR) have not been detected to date. Also, the mechanisms underlying malaria protection by RBC enzyme deficiencies are not clear. So, the objectives of this study were: to investigate malaria associated genetic traits in Cape Verde; to look for selection signatures in the PKLR gene region in African populations; to determine PK deficiency frequency and identify a prevalent PK variant that could be under selection by malaria in endemic African regions; to assess parasite invasion and maturation of Plasmodium falciparum growing in vitro in PK and G6PDdeficient and normal RBC; and to analyze the proteomic profile of non-infected and infected PK and G6PD-deficient and normal RBC as well as of parasites isolated from both deficient and normal host cells. In Cape Verde (epidemic area), no malaria selection signatures were found. However, when the analysis was performed in two malaria endemic countries (Angola and Mozambique), several selection marks were detected: data from Short Tandem Repeat (STR) and Single Nucleotide Polymorphic (SNP) loci spread along the PKLR gene region showed considerably higher differentiation between African and European (Portuguese) populations than that usually found for neutral markers, and a wider region showing strong Linkage Disequilibrium (LD) was found in the uncomplicated malaria group (and not in severe malaria group), suggesting that malaria may be shaping this genomic region in malaria countries. Additionally, when we performed the first study concerning the determination of PK deficiency prevalence in the African continent (in Mozambique), we were surprised with a high value: 4.1%. This was the higher frequency ever obtained for PK deficiency worldwide. Then, we looked for a mutation that could be in the origin of this phenotype and the missense mutation 829G>A (277Glu>Lys) was significantly associated. When we did a research of this mutation in other African countries (Angola, Sao Tome and Principe and Equatorial Guinea), the heterozygous carrier frequency was 2.6-6.7%, which is also among the highest heterozygous frequencies associated to PK deficiency described so far. We could not conclude about the association of PK deficiency and allele 829A with malaria outcome due to low sample number. Parasite invasion/maturation assays suggested that, in deficient RBC, the invasion step (or the cellular membranes) are more relevant for protection than maturation (the intracellular environment). Proteomic data from parasites growing in both G6PD and PK-deficient RBC revealed a distinct response from parasites growing in both deficient conditions, proportional to the phenotype severity. In parasites growing in G6PDdeficient RBC (asymptomatic individual), the main alteration was the increase of parasitic heat shock proteins and chaperones, showing that parasites are responding to oxidative stress conditions increasing the expression of protective molecules. In PKdeficient (transfusion-dependent individual with regular hemolytic crisis), a wider range of proteins displayed abundance alterations, the majority being down-expressed. The most represented biological processes in this response were hemoglobin digestion and protein trafficking/RBC remodeling. A high proportion of these altered proteins are related to Maurer’s clefts, which play important roles in the pathology of malaria infection. We hypothesized that protection against malaria in PK-deficient RBC is associated with the RBC membrane remodeling process by the parasite, which may lead to a reduction in invasion by new parasites and malaria virulence itself. Data on the RBC proteome will contribute to confirm this hypothesis.
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Hardee, Angelica. "Association of Malaria Control Methods and Healthcare Access among Pregnant Women in the Democratic Republic of the Congo." University of Cincinnati / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1490350707310335.
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Fry, Andrew E. "Genome mapping of malaria resistance genes : the host ligands of PfEMP1." Thesis, University of Oxford, 2009. http://ora.ox.ac.uk/objects/uuid:df1ffe4b-ba67-4fc6-9024-b278b887d4f9.
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Erythrocytes infected by mature forms of the Plasmodium falciparum parasite adhere to other components of the vascular space, a behavior considered critical to the pathogenesis of severe malaria. Adhesion is mediated by the P. falciparum erythrocyte membrane protein 1 (PfEMP1), a highly variant antigen expressed by the parasite and subject to switching during the course of an infection. The host ligands of PfEMP1 include CD36, ICAM-1 and the ABO antigens. By employing a series of population- and family-based association studies from multiple African populations, we examined whether variation in the genes underlying these molecules affects susceptibility to severe malaria. Our results suggest that a common frameshift mutation in the ABO glycosyltransferase, responsible for blood group O, is associated with protection from severe malarial phenotypes (P=2x10⁻⁷), particularly severe malarial anaemia. However, we found no significant disease associations with variation in either the ICAM1 or CD36 genes. We focused on two particular functional polymorphisms, the missense ICAM-1Kilifi and the CD36 nonsense mutation T1264G. We genotyped both markers in around 10,000 individuals, but neither demonstrated an association with severe malarial phenotypes. Malaria has been a profound selection pressure shaping human genetic diversity. The last decade has seen the development of several haplotype-based methods to detect signatures of recent positive evolutionary selection. These techniques are potentially invaluable tools in our hunt for genetic variants that protect from life threatening malaria. We used simulations and empirical data from the International HapMap Project to demonstrate the validity of searching for long regions of haplotype homozygosity, as an approach to finding alleles undergoing selective sweeps. We analysed genetic data from a range of populations, particularly those utilized by HapMap, to investigate whether our candidate genes were associated with signals of recent positive selection. We characterized the distribution of a selection event associated with the CD36 1264G allele, focused in Central-West Africa, and demonstrated a novel signal of low population differentiation at the ABO gene, suggestive of longstanding balancing selection. Our work confirms that variation in the host ligands of PfEMP1 modulates severe malaria susceptibility, and highlights the value of using signals of selection, along with functional experiments and genetic association studies, to dissect the biology of severe malaria.
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Baaklini, Sabrina. "Compréhension de la résistance humaine au paludisme : des études génétiques aux approches fonctionnelles." Thesis, Aix-Marseille, 2017. http://www.theses.fr/2017AIXM0384/document.
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La sévérité du paludisme est influencée par des interactions complexes entre de nombreux facteurs dont la génétique de l’hôte. Plusieurs études de liaison génétique menées dans différentes ethnies africaines ont montré une liaison entre le locus 6p21 et le paludisme simple. De plus, différents variants au sein des gènes TNF et NCR3, retrouvés dans ce locus, ont été indépendamment associés à ce phénotype au Burkina Faso.Ainsi, nous nous sommes tout d’abord intéressés aux polymorphismes du TNF. Nos résultats montrent que les variants TNF-308, TNF-244, et TNF-238 sont associés à la parasitémie maximale ou aux accès simples au Congo. Les approches moléculaires indiquent que le TNF-244 a un effet cis-régulateur avec une activité promotrice réduite en présence du variant A ainsi qu’une fixation altérée de protéines nucléaires en présence de ce même variant. Enfin, nos analyses bio-informatiques suggèrent que le TNF-244 et le TNF-238 agissent en synergie pour modifier le site de fixation d’au moins un facteur de transcription.Nous avons ensuite confirmé l’association du NCR3-412 avec le paludisme simple et le nombre d’accès fébrile au Congo. Les analyses fonctionnelles montrent que ce SNP a aussi un effet cis-régulateur avec une activité promotrice accrue en présence de l’allèle G et une liaison altérée de deux complexes protéiques en présence de l’allèle C. Les approches in silico et in vitro indiquent que les facteurs STAT4 et RUNX3 sont ceux dont la fixation est altérée.NCR3-412 altérant la résistance à la forme simple du paludisme, nous avons souhaité déterminer s’il est aussi impliqué dans la résistance au paludisme sévère mais nous n’avons détecté aucune associationThe severity of malaria is influenced by complex interactions between many factors including host genetics. Numerous genetic studies conducted in different African ethnic groups have shown a significant linkage between the 6p21 locus and mild malaria attack. In addition to their linkage, several polymorphisms found under the linkage peak, and more precisely within TNF and NCR3, were also independently associated with different sub-phenotypes of mild malaria in Burkina Faso.Thus, we first focused on TNF polymorphisms. Among the 4 polymorphisms analyzed, we found associations between TNF-238, TNF-244, TNF-308 and either mild malaria attack or maximum parasitemia. Molecular approaches showed that TNF-244 has a cis-regulatory effect. Indeed, we observe a decreased promoter activity and an altered binding of nuclear proteins in the presence of the A variant. In addition, our bioinformatics analyses suggested a cooperative effect of TNF-244 and TNF-238 in modifying the binding of at least one transcription factor.We then confirmed the association of NCR3-412 with both mild malaria and the number of febrile episodes in Congo. Functional analyses have shown that this SNP has also a cis-regulatory effect with a decreased promoter activity and an altered binding of two nuclear protein complexes in the presence of the C allele. Finally, in silico and in vitro approaches indicated that STAT4 and RUNX3 are the two transcription factors affected.As NCR3-412 is associated with resistance to mild malaria, we therefore investigated whether this SNP is also involved in severe malaria resistance, but we did not detect any association neither with severe anemia nor with cerebral malaria
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Griffiths, Michael J. "Integrated approach to identifying genes critical in the response to malaria using gene expression profiling and disease association analyses." Thesis, University of Oxford, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.491498.
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Ventura, Marcielle Teixeira. "Emulsões pediátricas de artesunato associado com cloridrato de mefloquina no tratamento da malária: desenvolvimento e estudo de estabilidade." Niterói, 2017. https://app.uff.br/riuff/handle/1/3350.
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A Malária é uma doença tropical muito importante em saúde pública devido às altas taxas de morbidade e mortalidade no mundo. Essa doença ocorre principalmente nas regiões africanas, sudeste asiático e mediterrâneo oriental. No Brasil, a Malária é predominante na região amazônica. Essa doença se manifesta nas formas mais graves principalmente em crianças menores de 5 anos. De forma semelhante, no Brasil, a maior prevalência da doença ocorre em crianças na faixa etária de 0 a 14 anos. A terapêutica antimalárica em crianças tem uma prática difícil, pois não existem apresentações farmacêuticas dos fármacos recomendados em dosagens flexíveis por via oral. O Guia de Tratamento da Malária no Brasil (2010) preconiza que a terapia de Malária falciparum em crianças de 06 a 11 meses de idade seja com comprimidos de Artesunato/Cloridrato de Mefloquina (AS/MQ) 25/55 mg durante 3 dias. Nessa faixa etária, formas farmacêuticas líquidas são as mais adequadas para serem utilizadas em pediatria devido à dificuldade desses pacientes em deglutir comprimidos e cápsulas, além dessas preparações apresentarem maior flexibilidade no ajuste da dose e são mais fáceis de administrar. O presente trabalho realizou o desenvolvimento farmacotécnico e estudo de estabilidade de uma formulação de emulsão a/o a partir de comprimidos de AS/MQ 25/55mg, através de transformação de forma farmacêutica (TFF), a ser manipulada em ambiente hospitalar. Para atender as condições necessárias para estabilidade de AS e mascaramento do sabor desagradável da MQ foi necessário o desenvolvimento de um veículo que pudesse receber os comprimidos de AS e MQ na forma de uma emulsão a/o. O veículo obtido teve como restrição técnica à utilização de substâncias que, nas concentrações utilizadas, não apresentassem efeitos tóxicos a pacientes pediátricos. O veículo emulsionado obtido apresenta em sua formulação sílica coloidal, óleo de girassol, sacarina, butil hidroxi tilueno (BHT), Span 80 e água destilada apresentando o aspecto, homogeneidade e consistência que permite a administração oral em copos dosadores ou seringas. O estudo de estabilidade físico do veículo emulsionado indicou que ele permaneceu estável por 30 dias quando armazenado a temperatura de 4ºC (± 2). No estudo analítico requerido para este trabalho, foi desenvolvida e validada a metodologia cromatográfica que permite a identificação e quantificação concomitante de AS e MQ. A metodologia cromatográfica desenvolvida apresenta todos os critérios necessários para o método válido aplicado em CLAE e demonstrou que pode ser utilizado nas duas formas farmacêuticas testadas, comprimidos e emulsão. A emulsão medicamentosa foi preparada pela incorporação dos comprimidos pulverizados ao veículo emulsionado, sem a adição de adjuvantes técnicos, obtendo-se uma emulsão medicamentosa de AS/MQ a 25/55mg por 3mL. Essa emulsão medicamentosa, durante o estudo de estabilidade, demonstrou que as características físicas estudadas são mantidas durante o período de 3 dias, tempo de tratamento da Malária em crianças de 06 a 11 meses com estes fármacos preconizado pelo Ministério da Saúde do Brasil e apresenta condições de manter a estabilidade química tanto do AS quanto do MQ. Para tanto, a emulsão medicamentosa de AS/MQ a 25/55mg por 3mL desenvolvida neste trabalho deve ser mantida a temperatura entre 4 e 25 ºC
Malaria is an important tropical disease in public health due to high rates of morbidity and mortality worldwide. This disease occurs mainly in Africa, Southeast Asia and Eastern Mediterranean. In Brazil, Malaria is prevalent in the Amazon region. This disease manifests in more severe forms mostly in children less than 5 years. Similarly, in Brazil, the highest prevalence of the disease occurs in children aged 0 to 14 years. Antimalarial therapy in children is a difficult practice because there are no pharmaceutical presentations of recommended dosages in flexible oral drugs. The Guide Treatment of Malaria in Brazil (2010) recommends that therapy of falciparum malaria in children 06-11 months of age either with tablets Artesunate / Mefloquine Hydrochloride (AS/MQ) 25/55 mg for 3 days. In this age range, liquid dosage forms are most suitable for use in pediatric patients due to difficulty these patients have in swallowing these tablets, in addition to these preparations having greater flexibility in adjusting the dose and they are easier to administer. The present work the pharmaceutics development and stability study of a w/o emulsion formulation from tablets of AS/MQ 25/55 mg through transformation of pharmaceutical forms (TPF) to be handled in a hospital environment. To meet the necessary stability of AS and masking of unpleasant taste of MQ, conditions required the development of a vehicle could receive the tablets of AS and MQ in the form of w/o emulsion. The vehicle was obtained as a technical restriction on the use of substances, at the concentrations used, it did not show any toxic effects to pediatric patients. The emulsified vehicle has obtained in the formulation colloidal silica, sunflower oil, sugar, butyl hydroxy toluene (BHT), Span 80 and distilled water have all the appearance, uniformity and consistency that allow oral administration in feeders cups or syringes. The study of the physical stability of the emulsified vehicle indicated that it remained stable for 30 days when it stored at 4ºC (± 2). In the analytical study required for this work, was developed and validated chromatographic method that allows the identification and simultaneous quantification of AS and MQ. The developed chromatographic method presents all necessary criteria for a valid method applied in HPLC and it demonstrated that can be used in tested dosage forms, tablets and emulsion. The drug emulsion was prepared by incorporation of the powdered tablets emulsified vehicle, without the addition of adjuvant technical, obtaining a drug emulsion AS/MQ 25/55mg by 3mL. This drug emulsion during the stability study showed that the physical properties studied are maintained during the 3 days, malaria treatment time in children 06-11 months on these drugs recommended by the Ministry of Health of Brazil. This drug emulsion presents conditions to maintain the chemical stability of both: the AS and MQ. Therefore, the drug emulsion AS/MQ 25/55mg by 3mL developed in this work, the temperature should be kept between 4 and 25ºC
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Cederlund, Julia. "Association between maternal level of education and the treatment with antimalarial drugs in children under the age of 5 in Nigeria : A cross-sectional study." Thesis, Uppsala universitet, Internationell mödra- och barnhälsovård (IMCH), 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-414328.
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Background Malaria is a major threat to global public health, with adverse health effects. Nigeria alone accounts for 25% of the global burden of malaria. Children are especially vulnerable to malaria, and if the disease is not treated it could have fatal consequences. Mothers have an important role in ensuring that adequate and timely treatment is given to the child. Aim The aim of this study was to investigate whether there was an association between maternal level of education and the treatment with antimalarial drugs in malaria positive children under-5 in Nigeria. Methods This study was a cross-sectional study that utilized Demographic and Health Surveys (DHS) data from the 2015 Nigeria Malaria Indicator Survey. Data on 2’622 malaria positive children were used, and a logistic regression analysis was conducted to determine the association with maternal level of education. Results The mothers with a higher level of education had two times higher odds (OR 2.31, CI 1.62- 3.32) of making sure their child received treatment with antimalarial drugs, compared to the mothers with no education. With an increase of 38% (OR 1.38, CI 1.11-1.71) in the odds for the child receiving treatment with antimalarial drugs if the mother has primary education and an increase of 51% (OR 1.51, CI 1.24-1.84) if the mother has secondary education compared to mothers with no education. Conclusion Mothers with a higher level of education waere more likely to make sure that their child received treatment with antimalarial drugs, compared to the mothers with no education.
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Neumayr, Andreas Vipa Thanachartwet. "Malarial acute renal failure at Mae Sot general hospital, Thailand : outcome and associated risk factors for death and dialysis /." Abstract, 2008. http://mulinet3.li.mahidol.ac.th/thesis/2551/cd414/5038610.pdf.
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Thematic Paper (M.C.T.M. (Clinical Tropical Medicine))--Mahidol University, 2008.LICL has E-Thesis 0038 ; please contact computer services. LIRV has E-Thesis 0038 ; please contact circulation services.
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Sikora, Martin. "Evolutionary genetics of malaria: genetic susceptibility and natural selection." Doctoral thesis, Universitat Pompeu Fabra, 2010. http://hdl.handle.net/10803/7220.
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Una de les forces selectives més fortes que han afectat a les poblacions humanes en la història més recent és el paràsit de la malària: Plasmodium falciparum, que és la causa de varis exemples d'adaptació induïda per patògens en els éssers humans. Una forma especial de malària és l'associada a l'embaràs, que es caracteritza per l'acumulació d'eritròcits infectats en la placenta, i que pot arribar a causar fins a 200.000 morts maternoinfantils cada any. L'objectiu d'aquest treball és descriure com aquesta forma peculiar de malària ha afectat la variació genètica humana. Amb aquesta finalitat, hem utilitzat mètodes tant de la genètica evolutiva com de l'epidemiologia molecular, resultant en la primera investigació a gran escala de la base genètica de la malària placentària. Els resultats ofereixen una nova visió sobre els gens que modulen el risc d'infecció, ,així com de la selecció natural actuant sobre les vies cel·lulars implicades en la patogènesi de la malaltia. Finalment, també aportem noves dades sobre l'estructura genètica de les poblacions sub-saharianes analitzades.One of the strongest selective forces affecting human populations in recent history is the malaria parasite Plasmodium falciparum, which is the cause of a variety of well-established examples of pathogen-induced adaptation in humans. A special form of malaria is pregnancy-associated malaria, which is characterised by the accumulation of infected erythrocytes in the placenta, and causes up to 200,000 maternal and infant deaths every year. The aim of this work is to characterise how this particular form of malaria has shaped human genetic variation. To that end we use methods of both evolutionary genetics and molecular epidemiology, reporting the first large-scale investigation of the genetic basis of placental infection. Our results provide new insights into genes modulating the risk of infection, as well as natural selection acting on cellular pathways involved in the pathogenesis of the disease. Finally, we also provide new data on the genetic structure of affected populations in Sub-Saharan Africa.
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Ernst, Kacey C., Steven Erly, Charity Adusei, Melanie L. Bell, David Komla Kessie, Alberta Biritwum-Nyarko, and John Ehiri. "Reported bed net ownership and use in social contacts is associated with uptake of bed nets for malaria prevention in pregnant women in Ghana." BIOMED CENTRAL LTD, 2017. http://hdl.handle.net/10150/622728.
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Background: Despite progress made in the last decades, malaria persists as a pressing health issue in sub-Saharan Africa. Pregnant women are particularly vulnerable to infection and serious health outcomes for themselves and their unborn child. Risk can be mitigated through appropriate use of control measures such as insecticide-treated bed nets. Although social networks can influence uptake of preventive strategies, the role of social influence on bed net ownership has not been explored. During an evaluation of a bed net distribution programme, the influence of non-health care advisors on ownership and use of bed nets by pregnant women in Kumasi, Ghana was examined. Methods: Data were collected through in-person interviews with 300 pregnant women seeking antenatal care in an urban hospital in Kumasi, Ghana. Participants were asked about their bed net ownership, bed net use, and information about three personal contacts that they go to for pregnancy advice. Information about these advisors was combined into an influence score. Logistic regression models were used to determine the association between the score and bed net ownership. Those who owned a bed net were further assessed to determine if interpersonal influence was associated with self-reported sleeping under the bed net the previous night. Results: Of the 294 women in the analysis, 229 (78%) reported owning bed nets. Of these bed net owners, 139 (61%) reported using a bed net the previous night. A dose response relationship was observed between the interpersonal influence score and bed net ownership and use. Compared to the lowest influence score, those with the highest influence score (> 1 SD above the mean) were marginally more likely to own a bed net [OR = 2.37, 95% CI (0.87, 6.39)] and much more likely to use their bed net [5.38, 95% CI (1.89, 15.25)] after adjusting for other factors. Conclusions: Interpersonal influence appears to have modest impact on ownership and use of bed nets by pregnant women in an urban area of Ghana. Further investigations would need to be conducted to determine if the relationship is causal or if individuals who associate are simply more likely to have similar practices.
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Frank, Clemens [Verfasser]. "Spatial heterogeneity of malaria in Ghana : a cross-sectional study of the association between urbanicity and the acquisition of immunity / Clemens Frank." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2016. http://d-nb.info/1119803411/34.
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Kern, Selina Melanie [Verfasser], and Gabriele [Gutachter] Pradel. "Functional characterization of splicing-associated kinases in the blood stages of the malaria parasite Plasmodium falciparum / Selina Melanie Kern. Gutachter: Gabriele Pradel." Würzburg : Universität Würzburg, 2015. http://d-nb.info/1111508720/34.
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Brisebarre, Audrey. "Recherche de facteurs génétiques impliqués dans la résistance au paludisme et au sepsis : études pangénomiques de liaison génétique et d'association, intégration des résultats d' association aux réseaux d' intéractions protéine-protéine." Thesis, Aix-Marseille, 2014. http://www.theses.fr/2014AIXM4072.
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Le paludisme et le sepsis sont des maladies infectieuses très répandues causant plusieurs centaines de milliers de morts tous les ans. Elles sont toutes deux multifactorielles. Les devenirs de ces infections sont influencés par des facteurs environnementaux, par des facteurs sociaux-économiques, politiques et comportementaux mais aussi par des variables dépendant du patient comme son âge. De nombreux arguments existent en faveur d'un contrôle génétique de la résistance au paludisme et au sepsis. Ces deux maladies sont considérées comme proches par les spécialistes car leur physiopathologie est liée notamment à une inflammation systémique non contrôlée responsable des formes les plus graves. Afin d'identifier de nouveaux gènes potentiellement impliqués dans la résistance à ces deux maladies, nous avons effectué des études génétiques pangénomiques dans deux populations vivant en zone endémique pour le paludisme à Plasmodium falciparum au Burkina-Faso et dans une cohorte de patients atteints de sepsis.Enfin nous avons réalisé les deux premières études d'association pangénomiques identifiant des associations significatives avec la mortalité suite à un choc septique. Nous avons obtenu 32 SNPs significativement associés à la mortalité précoce et 108 significativement associés à la mortalité tardive. Le réseau des interactions protéine-protéine impliquant les protéines codées par les gènes associés a permis d'établir une liste non exhaustive des fonctions altérées durant le choc septique, notamment liées à la réponse immune, et a révélé, malgré les différences au niveau des gènes impliqués, un mécanisme commun participant à la susceptibilité précoce et tardive au choc septiqueMalaria and sepsis are widespread infectious diseases causing hundreds of thousands deaths each year. There is a growing body of evidence for a genetic control of malaria and sepsis resistance. Both diseases are considered close because they are characterized by a systemic inflammation, some common organ dysfunctions, and disorders of coagulation. In order to identify new genes potentially involved in disease resistance, we performed genomewide genetic studies in two populations living in endemic regions for Plasmodium falciparum malaria in Burkina-Faso and in a cohort of septic shock patients. Genetic linkage studies revealed significant genetic linkages on chromosome 6p21.3 and 17p12 with, respectively, mild malaria and asymptomatic parasitaemia. We also performed the first genetic linkage studies concerning immunoglobulin G and their sub-classes against Plasmodium falciparum antigens. We detected significant linkages of IgG3 sub-class with chromosomes 8p22-p21 and 20q13 and between IgG4 sub-class and chromosome 9q34. Finally we performed the first two genomewide association studies identifying significant associations with all-causes mortality after a septic shock. We identified 32 SNPs significantly associated with early mortality and 108 SNPs significantly associated with late mortality. We identified a protein-protein network containing proteins associated with both early and late mortality. Furthermore, the network of protein-protein interactions involving proteins encoded by associated genes allowed us to establish a list of some altered functions during septic shock, most of them being related to the immune responses or the renin-angiotensin-aldosterone system
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Pereira, Marcelo Luís Monteiro. "O papel da heme oxigenase 1 na síndrome do desconforto respiratório agudo associada à malária." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/42/42133/tde-11112016-154538/.
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A malária é uma doença causada pelo parasita do gênero Plasmodium e que foi responsável por cerca de 440.000 mortes em 2015. A síndrome do desconforto respiratório agudo (SDRA) é uma das principais complicações clínicas da malária. O modelo murino DBA/2 reproduz os sinais clínicos da SDRA observados em humanos, quando infectado com o Plasmodium berghei ANKA. Além disso, altos níveis da enzima heme oxigenase 1 (HO-1) foram observados em casos de malária cerebral e em SDRA em humanos. Os nossos dados indicam que os níveis da HO-1 estão aumentados em camundongos que desenvolvem SDRA associada à malária (SDRA-AM). Adicionalmente, a droga indutora de HO-1 (hemina) aumentou a sobrevivência e preveniu a SDRA-AM. Verificou-se também uma redução na permeabilidade pulmonar e nos níveis de VEGF, além de uma melhoria nos parâmetros respiratórios em animais tratados com hemina. Assim sendo, a indução da HO-1 antes do desenvolvimento da SDRA-AM é protetora e assim, a HO-1 pode ser um alvo de novos fármacos, como forma de prevenir o desenvolvimento da SDRA-AM em humanos.Malaria is a serious disease, caused by the parasite of the genus Plasmodium, which was responsible to 440,000 deaths in 2015. Acute lung injury/ acute respiratory distress syndrome (ALI/ARDS) is one of the main clinical complications in severe malaria. The murine model DBA/2 reproduces the clinical signs of ALI/ARDS observed in humans, when infected with Plasmodium berghei ANKA. Additionally, high levels heme oxygenase 1 (HO-1) were reported in cases of cerebral malaria and in ALI/ARDS in humans. Our data have indicated that the HO-1 levels are increased in mice that develop malaria associated ALI/ARDS (MA-ALI/ARDS). Additionally, a HO-1 inducing drug (hemin) increased the survival rate and prevented mice from developing MA-ALI/ARDS in treated mice. Also, there was a decrease in the lung permeability and in lung VEGF levels, and an amelioration of respiratory parameters. Therefore, the induction of HO-1 before the development of MA-ALI/ARDS is protective, making this enzyme a possible target of new drugs to prevent the development of MA-ALI/ARDS in humans.
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Kamaranzi, Bakunda Kaakaabaale. "Factors associated with late presentation of children under five and pregnant women with malaria for treatment at health units in Bungokho Health Sub District." Thesis, University of the Western Cape, 2010. http://etd.uwc.ac.za/index.php?module=etd&action=viewtitle&id=gen8Srv25Nme4_9025_1363357146.
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Background: Malaria is the leading cause of death of Uganda&rsquo
s children under 5 years of age and the number-one cause of illness in adults in Uganda. The success of malaria treatment strategies is closely linked to the behavior of patients and caretakers of young children. In the case of malaria this includes accessing appropriate treatment for
suspected malaria in time. In Bungokho Sub County, in spite of the efforts by district health workers and the Ministry of Health to implement the malaria control, prevention and treatment strategies, pregnant women and caretakers of children under 5 years of age continue to present late for treatment in the health units resulting in possible avoidable
death or disability. Aim and objectives: The aim of this study was to explore the factors that lead to late presentation of children and pregnant women with malaria for treatment at health units. This was done by exploring the perceptions of caregivers of children under five years and pregnant women on the community&rsquo
s knowledge and understanding of the
symptoms and treatment of malaria
and describing perceptions of caregivers and pregnant women on health care provision at the health units and alternative treatment for malaria. Methods :The study was conducted in Bungokho Health sub-district, in Mbale district, Eastern Uganda over a two month period in 2009. It was a descriptive exploratory study using qualitative research methods. Four focus groups were carried out, two with caregivers of children under 5 years and two with pregnant women, with each focus group consisting of eight participants. Two caregivers and two pregnant women were identified from the focus groups for further indepth interviews. Four in-depth interviews were conducted with health unit staff from Bungokho HCVI. Notes were taken and observations made during the focus groups and interviews. The proceedings were audio-taped and recordings used to expand and clarify notes. Thematic content analysis was used to analyze the data and identify recurrent themes from the focus group discussions and
interviews of the reasons for late presentation for malaria treatment. Results: All caregivers were women, a significant majority of whom were peasants who had not gone beyond the primary education. Caregivers were aware of the general symptoms of malaria but associated more serious or dangerous symptoms with other causes including
witchcraft. Pregnant women, on the other hand, seemed to have sound knowledge of both the general and dangerous symptoms of malaria and were likely to attend the health
units timeously for reatment. Religious beliefs and practices, particularly belief in the healing ability of prayers prevented early reporting of malaria cases to health units leading
to late presentation. Alternative treatment of malaria from traditional herbalists was also sought by the communities particularly when the intensity of malaria was at its peak during the rainy season. Poverty in the community seemed to play a big role in shaping community preference for treatment sources, as well as early presentation to the health
units. It was found that the anticipated cost of laboratory tests and sundries at the health units deterred caregivers from taking children under five to health units. There was therefore a strong reliance (and preference for) community medicine distributor&rsquo
s (CMDs) because of free services and easy access. Lack of support from spouses (in particular husbands) coupled with the rude behavior of health workers towards caregivers and pregnant women discouraged visits to health units. The long waiting time and intermittent drug stock-outs also created a negative perception of service at the health units. Conclusions and recommendations: There is need for further sensitization of communities on the need to seek prompt treatment for children under five years of age at the health units (that is, within 24 hours of the onset of fever). Training and supervision of CMDs should be strengthened to ensure consistent supply of drugs, correct dosage of anti-malarial medication and improvements in the referrals to the health units. In order to improve
service delivery at the health units, there is need to review and strengthen human resource management of the health units, including staffing requirements and management
practices, such as support and supervision, patient care standards and client feedback mechanisms. It is also important that there are adequate stocks of anti-malarial drugs
and laboratory supplies at health units.
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Dgedge, Martinho do Carmo. "Implementation of an insecticide treated bednet programme for malaria prevention through the primary health care system in Mozambique : socioeconomic factors associated with sustainability and equity." Thesis, London School of Hygiene and Tropical Medicine (University of London), 2000. http://researchonline.lshtm.ac.uk/682299/.
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Malaria is the principal cause of morbidity and mortality in Mozambique, accounting for more than 40% of the attendance in the public health clinics. Insecticide-treated bednets; (ITNs) have proved to be a cost-effective means of preventing of malaria. Most previous ITN projects have been implemented in pilots or trials and with substantial financial, human and technical resources. Presently however, in many African countries services can no longer be provided "free" (at no charge to users). There is still a lack of knowledge of how financially sustainable and equitable a cost-sharing ITN programme implemented through the primary health care system would be. In Mozambique no ITNs were available, and very few households had bednets before the start of this study. Thus before introducing an ITN programme in Mozambique, it was important to evaluate whether the primary health care system could deliver ITNs, and to determine how sustainable and equitable such a programme would be. The study which forms the basis for this thesis took place in Boane, Mozambique from, 1996 to 1998. The aim of the study was to determine how financially sustainable and equitable an ITN programme could be when implemented through the primary health care system, and how the socio-economic level of the community would affect such a programme. Bednets were treated with Lambdacyalothrin and sold at the health centre at price equal to the factory's wholesale price. The willingness to pay of the households, the ITN coverage which was achieved, the total cost of implementing the project, and the financial resources which would be required to implement a national ITN programme in Mozambique were calculated. The main findings of the study were as follows: - The Boane community accepted the ITNs very well. However, the purchase of ITNs was dependent on the socio-economic level of the buyer; poor households were less likely to buy than richer households (p<0.001). Thus, there was not an equitable distribution of ITNs in the community. - Many households whose stated maximum willingness to pay before the project was less than US$5 actually did pay that amount for an ITN during the project. Thus, willingness to pay was not a reliable way of predicting the households' probable purchase of ITNs. - The estimate of the cost of the project demonstrated that the financial cost per ITN delivered ($9.60) was much higher than the price at which the ITNs were sold to the consumers ($5 on average). Thus, the project was not financially sustainable. Moreover, given the cost structure covering a larger area or achieving wider coverage would have required an even higher level of subsidy. - In order to guarantee an equitable national ITN programme through the public health system in Mozambique, the govermnent will have to mobilise external donors to fmance the ITN programme. This study contributes to an understanding of the implications of how the price of ITNs affects the financial sustainability, equity and coverage of the programme, and makes recommendations for obtaining the funds required to heavily subsidise ITN programmes in Mozambique in particular, and in Sub-Saharan Africa in general.
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Strauß, Christina Verfasser], and Julia [Akademischer Betreuer] [Kehr. "Genetic fine mapping and functional analysis of a chromosomal region within ATP2B4 associated with resistance against severe malaria in humans / Christina Strauß ; Betreuer: Julia Kehr." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2020. http://nbn-resolving.de/urn:nbn:de:gbv:18-86637.
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Strauß, Christina [Verfasser], and Julia [Akademischer Betreuer] Kehr. "Genetic fine mapping and functional analysis of a chromosomal region within ATP2B4 associated with resistance against severe malaria in humans / Christina Strauß ; Betreuer: Julia Kehr." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2020. http://d-nb.info/1209676133/34.
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Dwivedi, Ankit. "Functional analysis of genomic variations associated with emerging artemisinin resistant P. falciparum parasite populations and human infecting piroplasmida B. microti." Thesis, Montpellier, 2016. http://www.theses.fr/2016MONTT073/document.
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Le programme d’élimination du paludisme de l’OMS est menacé par l’émergence etla propagation potentielle de parasites de l’espèce Plasmodium falciparum résistants à l’artémisinine. Récemment il a été montré que (a) des SNPs dans une région du chromosome 13 subissaient une forte sélection positive récente au Cambodge,(b) plusieurs sous-populations de parasites de P. falciparum résistants et sensibles à l’artémisinine étaient présentes au Cambodge, (c) des mutations dans le domaine Kelch du gène k13 sont des déterminants majeurs de la résistance à l’artémisinine dans la population parasitaire cambodgien et (d) des parasites de sous-populations du nord du Cambodge près de la Thaïlande et du Laos sont résistants à la méfloquine et portent l’allèle R539T du gène de k13.Il est donc nécessaire d’identifier la base génétique de la résistance dans le but de surveiller et de contrôler la transmission de parasites résistants au reste du monde, pour comprendre le métabolisme des parasites et pour le développement de nouveaux médicaments. Ce travail a porté sur la caractérisation de la structure de la population de P. falciparum au Cambodge et la description des propriétés métaboliques des sous-populations présentes ainsi que des flux de gènes entre ces sous-populations. Le but est d’identifier les bases génétiques associées à la transmission et l’acquisition de résistance à l’artémisinine dans le pays.La première approche par code-barre a été développée pour identifier des sous-populations à l’aide d’un petit nombre de loci. Une approche moléculaire de PCR-LDR-FMA multiplexée et basée sur la technologie LUMINEX a été mise au point pour identifier les SNP dans 537 échantillons de sang (2010 - 2011) provenant de 16centres de santé au Cambodge. La présence de sous-populations le long des frontières du pays a été établie grâce à l’analyse de 282 échantillons. Les flux de gènes ont été décrits à partir des 11 loci du code-barre. Le code-barre permet d’identifier les sous-populations de parasites associées à la résistance à l’artémisinine et à la méfloquine qui ont émergé récemment.La seconde approche de caractérisation de la structure de la population de P.falciparum au Cambodge a été définie sur la base de l’analyse de 167 génomes de parasites (données NGS de 2008 à 2011) provenant de quatre localités au Cambodge et récupérés à partir de la base de données ENA. Huit sous-populations de parasites ont pu être décrites à partir d’un jeu de 21257 SNPs caractérisés dans cette étude. La présence de sous-populations mixtes de parasite apparait comme un risque majeur pour la transmission de la résistance à l’artémisinine. L’analyse fonctionnelle montre qu’il existe un fond génétique commun aux isolats dans les populations résistantes et a confirmé l’importance de la voie PI3K dans l’acquisition de la résistance en aidant le parasite à rester sous forme de stade anneau.Nos résultats remettent en question l’origine et la persistance des sous-populations de P. falciparum au Cambodge, fournissent des preuves de flux génétique entre les sous-populations et décrivent un modèle d’acquisition de résistance à l’artémisinine.Le processus d’identification des SNPs fiables a été ensuite appliqué au génome de Babesia microti. Ce parasite est responsable de la babésiose humain (un syndrome de type malaria) et est endémique dans le nord-est des Etats-Unis. L’objectif était de valider la position taxonomique de B. microti en tant que groupe externe aux piroplasmes et d’améliorer l’annotation fonctionnelle du génome en incluant la variabilité génétique, l’expression des gènes et la capacité antigénique des protéines. Nous avons ainsi identifié de nouvelles protéines impliquées dans les interactions hôte-parasiteThe undergoing WHO Malaria elimination program is threatened by the emergenceand potential spread of the Plasmodium falciparum artemisinin resistant parasite.Recent reports have shown (a) SNPs in region of chromosome 13 to be understrong recent positive selection in Cambodia, (b) presence of P. falciparum parasiteresistant and sensitive subpopulations in Cambodia, (c) the evidence that mutationsin the Kelch propeller domain of the k13 gene are major determinants ofartemisinin resistance in Cambodian parasite population and (d) parasite subpopulations in Northern Cambodia near Thailand and Laos with mefloquine drugresistance and carrying R539T allele of the k13 gene.Identifying the genetic basis of resistance is important to monitor and control thetransmission of resistant parasites and to understand parasite metabolism for the development of new drugs. This thesis focuses on analysis of P. falciparum population structure in Cambodia and description of metabolic properties of these subpopulations and gene flow among them. This could help in identifying the genetic evidence associated to transmission and acquisition of artemisinin resistance over the country.First, a barcode approach was used to identify parasite subpopulations using smallnumber of loci. A mid-throughput PCR-LDR-FMA approach based on LUMINEXtechnology was used to screen for SNPs in 537 blood samples (2010 - 2011) from 16health centres in Cambodia. Based on successful typing of 282 samples, subpopulations were characterized along the borders of the country. Gene flow was described based on the gradient of alleles at the 11 loci in the barcode. The barcode successfully identifies recently emerging parasite subpopulations associated to artemisinin and mefloquine resistance.In the second approach, the parasite population structure was defined based on167 parasite NGS genomes (2008 - 2011) originating from four locations in Cambodia,recovered from the ENA database. Based on calling of 21257 SNPs, eight parasite subpopulations were described. Presence of admixture parasite subpopulation couldbe supporting artemisinin resistance transmission. Functional analysis based on significant genes validated similar background for resistant isolates and revealed PI3K pathway in resistant populations supporting acquisition of resistance by assisting the parasite in ring stage form.Our findings question the origin and the persistence of the P. falciparum subpopulations in Cambodia, provide evidence of gene flow among subpopulations anddescribe a model of artemisinin resistance acquisition.The variant calling approach was also implemented on the Babesia microti genome.This is a malaria like syndrome, and is endemic in the North-Eastern USA. Theobjective was to validate the taxonomic position of B. microti as out-group amongpiroplasmida and improve the functional genome annotation based on genetic variation, gene expression and protein antigenicity. We identified new proteins involved in parasite host interactions
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LANDES, PAUL. "Syndrome de gougerot-sjogren, cancer bronchopulmonaire a petites cellules, syndrome de lambert-eaton chez un meme malade : cette association est-elle fortuite ?" Toulouse 3, 1988. http://www.theses.fr/1988TOU31221.
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Swan, Paul Lombard. "Synthesis of mixed ligand, water soluble square planar platinum (II) complexes and an investigation of their association with haematin and potential to inhibit the formation of synthetic malaria pigment." Master's thesis, University of Cape Town, 2002. http://hdl.handle.net/11427/9782.
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Includes bibliography.To establish their potential as a template for novel anti-malarial drugs, a series of planinum (II) complexes were synthesised, their association with haematin determined in 40 aqueous DMSO, pH 7.4 at 25°C and their ability to inhibit the formation of β-haematin (synthetic malaria pigment) was investigated. The compounds synthesised and investigated contained a platinum (II) ion coordinated to acylthiourea and diimine ligands. The diimines used included both substituted and unsubstituted 2,2’-bipyridines and 1,10-phenanthrolines. 2-phenyl pyridine was also utilised as a ligand. It has been shown that the uncoordinated planar ligands interact weakly with haematin with a log K in the range of 1.9 and 3.3 while the twisted or more sterically hindered ligands show no observable association with porphyrin. A series of complexes having platinum coordinated which was reflected in association constant log K values in the range of 4.8 to 5.8. Using a 1,10-phenanthroline ligand in place of a 2,2-bipyridine ligand increased the association constant of the platinum complex, resulting in this series of complexes having log K values in the range of 5.8 to 6.2. It has been shown that when platinum (II) is coordinated to diimines, it is the electron withdrawing properties of the metal which result in the strong association between the diimine containing complex and haematin. Finally both the complex containing platinum cis to two acylthiourea ligands as well as a platinum complex containing 2-phenyl pyridine were shown to have no observable interaction with haematin.
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Adukpo, Selorme [Verfasser], and Peter [Akademischer Betreuer] Kremsner. "Distribution of Knop blood group antigens and association of Triggering receptor expressed on myeloid cells 1 (TREM-1) gene variants in Ghanaian children with malaria / Selorme Adukpo ; Betreuer: Peter Kremsner." Tübingen : Universitätsbibliothek Tübingen, 2017. http://d-nb.info/1165579014/34.
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Adukpo, Selorme Verfasser], and Peter [Akademischer Betreuer] [Kremsner. "Distribution of Knop blood group antigens and association of Triggering receptor expressed on myeloid cells 1 (TREM-1) gene variants in Ghanaian children with malaria / Selorme Adukpo ; Betreuer: Peter Kremsner." Tübingen : Universitätsbibliothek Tübingen, 2017. http://d-nb.info/1165579014/34.
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Milet, Jacqueline. "Étude de la composante génétique de la variabilité des infections palustres simples : Approche génome entier dans deux cohortes de jeunes enfants au Bénin First Genome-Wide Association Study of Non-Severe Malaria in Two Birth Cohorts in Benin Mixed logistic regression in Genome-Wide Association Studies." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASR013.
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Malgré les moyens importants de prévention et de lutte mis en place ces dernières années, le paludisme reste dévastateur avec près d’un demi-million de décès par an (405 000 en 2018, d'après le dernier rapport de l'OMS). Le rôle clé joué par les facteurs génétiques de l’hôte dans la susceptibilité et la sévérité de la maladie est admis aujourd'hui. Cependant, les bases moléculaires de la sensibilité/résistance au paludisme restent encore mal connues. Ces dix dernières années, les efforts de recherches pour l’identification de gènes impliqués dans la sensibilité au paludisme à P. falciparum se sont concentrés sur les formes graves de paludisme, avec plusieurs plusieurs études d’association sur l’ensemble du génome (Genome-Wide Association Study ou GWAS) publiées. Ce manuscrit porte sur l’extension de cette approche aux formes simples du paludisme, au travers de l’étude d’association génome entier de deux cohortes de nouveau-nés au Sud Bénin (au total 800 enfants), suivis pendant 18-24 mois par l’UMR261 (MERIT IRD/Université de Paris). Dans une première partie nous présentons les résultats de la première GWAS réalisée sur les formes simples de paludisme dans ces deux cohortes. L’association a été testée avec la récurrence des accès palustres et la récurrence de l’ensemble des infections (incluant les accès palustres et les infections asymptomatiques) en prenant en compte un risque environnemental estimé au niveau individuel. Elle met en évidence plusieurs signaux d’association forts, en lien avec des gènes dont la fonction biologique est pertinente pour le paludisme (notamment PTPRT, MYLK4, UROC1 et ACER3). La forte variabilité génétique présente au sein des populations africaines a nécessité de prendre en compte l’effet de confusion potentiel de la structure de population. Dans l’étude les formes simples de paludisme, une approche en deux étapes a été utilisée, le modèle de Cox mixte, utilisé pour l’analyse des données longitudinales, n’étant pas applicable à l’ensemble du génome du fait du temps de calcul nécessaire. Un modèle de Cox mixte a été appliqué pour construire un « effet individuel » ajusté sur les covariables, puis un modèle mixte linéaire pour tester l’association avec les polymorphismes du génome. Ceci nous a conduits à nous intéresser plus généralement aux modèles mixtes non-linéaires. Deux méthodes permettant l’estimation de l’effet des polymorphismes avec le modèle logistique mixte sont proposées, qui pourront être dans le futur généralisé à d’autres modèles, dont le modèle de Cox. Dans une dernière partie, le paludisme ayant constitué une des plus fortes pressions de sélection que l’homme ait connue dans son histoire récente, nous explorons la possibilité d’exploiter l’information de sélection naturelle pour augmenter la puissance de l’analyse, et améliorer la détection des signaux d’association. L’analyse des signaux de sélection positive récente sur l’ensemble du génome a été réalisée avec plusieurs méthodes basées sur les haplotypes longs ((iHS, nsL and XP-EHH). Celle-ci met en évidence plusieurs régions chromosomiques d’intérêt potentiel où les signaux d’association et de sélection co-localisent ; mais confirme également la difficulté à mettre en évidence les signaux de sélection liés au paludisme avec les outils disponibles actuellementIn spite of numerous prevention and control efforts in recent years, malaria remains a major global public health problem with nearly half a million deaths per year (405,000 in 2018). The key role played by genetic factors of the host in the susceptibility and severity of the disease is is admitted nowadays. However, the molecular basis of susceptibility / resistance to malaria has not been elucidated to date. Over the past decade, research efforts to identify genes involved in malaria susceptibility have focused on severe malaria, with several genome-wide association studies (GWAS) published. This manuscript concerns the extension of this approach to uncomplicated forms of malaria, through the genome wide association study of two birth cohorts in South Benin (800 children), followed for 18-24 months by UMR261 (MERIT IRD / University of Paris).In the first part, we present the results of the first GWAS performed on simple forms of malaria in these two cohorts. The association was tested with the recurrence of malaria attacks and the recurrence of all infections (including malaria attacks and asymptomatic infections) taking into account an environmental risk estimated at the individual level. It highlights several strong association signals, linked to genes whose biological function is relevant for malaria (in particular PTPRT, MYLK4, UROC1 and ACER3). The high genetic diversity within African populations has made it necessary to take into account the potential confounding effect of population structure. In this study we proceeded with a two-step strategy as the Cox mixed model, used for the analysis of longitudinal data, is not applicable to the whole genome due to computational burden. In a first step, an analysis was performed with a Cox mixed model to build an "individual effect" fitted on the covariates, then a linear mixed model were used to test the association with genome polymorphisms. This led us to focus more generally on non-linear mixed models. Two methods allowing the estimation of the effect of polymorphisms with the mixed logistic model are proposed, which may in the future be generalized to other models, including the Cox model.In a final part, malaria having been one of the strongest selection pressures that man has known in recent history, we explore the possibility of exploiting natural selection information to increase the power of analysis, and improve the detection of association signals. The analysis of recent positive selection signals were performed using several genome-scan methods focusing on patterns of long-range haplotype homozygosity (iHS, nsL and XP-EHH). This analysis revealed several chromosomic region of potential interest, where the signals of association and selection co-localized but confirms also the difficulty of highlighting the selection signals linked to malaria with tools currently available
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Nguyen, Thy Ngoc. "Prédisposition génétique au paludisme à Plasmodium falciparum : études d'association et analyses fonctionnelles de variants génétiques candidats situés dans des régions liées génétiquement au paludisme." Thesis, Aix-Marseille, 2015. http://www.theses.fr/2015AIXM4116.
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Dans cette thèse, nous avons étudié l'influence de plusieurs variants génétiques situés dans les régions chromosomiques 5q31-q33, 6p21, et 17p12, pour lesquelles une liaison génétique avec des phénotypes de paludisme a été montrée.Les gènes NCR3 et TNF, qui sont situés dans la région chromosomique 6p21, ont été associés au paludisme dans une population vivant au Burkina Faso. Nous avons répliqué ces études dans une population congolaise afin deconfirmer les associations des polymorphismes avec les accès palustres simples et la parasitémie symptomatique. Nos résultats montrent que le polymorphismeNCR3-412 est associé avec les accès palustres simples au Congo, et que les polymorphismes TNF-308, TNF-244, et TNF-238 sont associés avec les accès palustres simples ou la parasitémie symptomatique. En outre, nos analyses bioinformatiques suggèrent que les polymorphismes TNF-244 et TNF-238 agissent en synergie pour modifier le site de fixation pour au moins un facteur de transcription.Les deux gènes HS3ST3A1 et HS3ST3B1, qui sont situés dans la région chromosomique 17p12, sont impliqués dans la biosynthèse des heparanes sulfates. Dans cette étude, nous avons étudié l'association d’un polymorphisme situé dans le promoteur de HS3ST3A1 avec les accès palustres simples et la parasitémie symptomatique, et n’avons détecté aucune association. Nous avons étudié en outre le gène NDST1, situé dans la région chromosomique 5q31-q33, et qui code également pour une enzyme impliquée dans la voie héparane sulfate. Des résultats préliminaires encourageants soutiennent l'hypothèse que la variation génétique de NDST1 influence la parasitémie asymptomatiqueIn this thesis, we investigated the influence of some genetic variants located within chromosomes 5q31-q33, 6p21, and 17p12, which have been shown to be linked to malaria phenotypes. The genes NCR3 and TNF, which are located in the chromosomal region 6p21, have been reported to be associated with malaria in Burkina Faso population. We have replicated those studies in Congolese population to evaluate the associations of the SNPs in those genes with mild malaria attack and Plasmodium parasitemia. The results showed that the variant NCR3-412 is associated with mild malaria in Congo, and TNF-308, TNF-244, and TNF-238 are associated with mild malaria attack, maximum parasitemia, or both. In addition, bioinformatic studies suggest that TNF-244 and TNF-238 synergise to alter the binding of transcription factors.The two genes HS3ST3A1 and HS3ST3B1, which are located in chromosomal regions 17p12, are involved in the heparan sulfate proteoglycan biosynthesis. In this study, we further investigated the association of the polymorphisms in these genes with mild malaria attack and maximum parasitemia. However no association was found. We further studied the NDST1 gene, which is located within chromosome 5q31-q33, and which encodes the bifunctional enzyme N-deacetylase/ N-sulfotransferase 1, and also participates in the heparan sulfate synthesis . Encouraging results support the hypothesis that NDST1 variation influence controlling parasitemia. Further association and functional studies are needed to validate the role of NDST1 in malaria infection. More generally, the enzymes involved in the heparan sulfate pathway might play a key role in controlling malaria infection
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Chauvet, Margaux. "Étude de la modulation, par l'hémoglobine S, de la présentation des antigènes plasmodiaux à la surface du globule rouge infecté par Plasmodium falciparum, et de la réponse immunitaire contre le paludisme Impact of hemoglobin S trait on cell surface antibody recognition of Plasmodium falciparum infected erythrocytes in pregnancy-associated malaria." Thesis, Sorbonne Paris Cité, 2019. http://www.theses.fr/2019USPCB037.
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Le paludisme est une maladie tropicale résultant de l'infection par le parasite Plasmodium falciparum transmis par piqûre de moustique. Les symptômes du paludisme résultent du développement de P. falciparum dans les globules rouges (GR). Depuis des siècles, le paludisme a exercé des pressions sur le génome humain, sélectionnant des mutations conférant une protection contre les formes sévères de la maladie. C'est le cas de la mutation du gène de l'hémoglobine (HbA), composant principal des GRs. La forme mutée du gène produit une hémoglobine anormale (HbS). Contrairement à la drépanocytose (HbSS), le portage hétérozygote (trait drépanocytaire) de cette mutation (HbAS) est asymptomatique. Les porteurs sains HbAS développent moins de symptômes graves du paludisme. Aujourd'hui, les mécanismes responsables de cette protection restent partiellement élucidés. Lors de son développement, P. falciparum modifie la membrane et le cytosquelette du GR afin d'exposer des protéines parasitaires à la surface de l'hématie. Parmi ces protéines, l'adhésine majeure parasitaire "P. falciparum erythrocyte membrane protein 1" (PfEMP1), se lie aux récepteurs endothéliaux, entraînant la cytoadhérence et la séquestration des GRs infectés (iGRs). Cette cytoadhérence permet d'éviter le passage et la clairance splénique des iGRs. Des études ont montré que les iGRs HbAS cytoadhèreraient moins, en association avec une présentation anormale de PfEMP1. Cette thèse porte sur l'étude des mécanismes de résistance du trait drépanocytaire contre le paludisme à P. falciparum. Le premier projet de cette thèse porte sur le phosphoprotéome des membranes de GRs HbAA et HbAS infectés par P. falciparum. Les protéines parasitaires exposées à la surface du GR interagissent avec des protéines érythrocytaires impliquées dans l'ancrage de la membrane du GR au cytosquelette. Il s'agit des protéines du complexe Ankyrine-R et du complexe jonctionnel. Le stress oxydant généré par le trait drépanocytaire et par l'invasion parasitaire perturbe l'équilibre kinase/phosphatase dans la cellule, pouvant entraîner des modulations de la phosphorylation des protéines, interférer dans les interactions protéiques et par conséquent dans la présentation des antigènes parasitaires. Des extraits membranaires de GRs HbAA et HbAS infectés ont été produits et analysés en spectrométrie de masse et en Western-Blot. Cette étude a montré que le trait drépanocytaire modulait la phosphorylation des protéines érythrocytaires de la membrane du iGR (transporteurs membranaires et protéines du cytosquelette majoritairement), mais aussi celle de protéines parasitaires. Le deuxième projet porte sur la réponse anticorps anti-VAR2CSA dans le cadre du paludisme gestationnel selon le portage de l'HbS. Le paludisme gestationnel est une des formes sévères du paludisme, due à la cytoadhérence des iGRs dans le placenta. Cette cytoadhérence résulte de l'interaction d'un PfEMP1 particulier, VAR2CSA, à la chondroïtine sulfate A des syncytiotrophoblastes. 159 plasmas de femmes HbAA et HbAS Béninoises, collectés à l'accouchement, ont été utilisés pour mesurer leur capacité de reconnaissance de VAR2CSA à la surface de GRs HbAA et HbAS infectés. La reconnaissance immune des iGRs HbAS par les plasmas provenant des mères HbAS est significativement plus faible que celle des iGRs HbAA par les plasmas des mères HbAA. Par ailleurs, d'autres maladies génétiques affectant le GR peuvent influencer la réponse en anticorps spécifiques aux GRs parasités. Les co-portages du déficit en G6PD et de l'alpha-thalassémie avec l'HbS ont ainsi été évalués pour ce groupe d'étude. Respectivement, 26,7% et 51,7% des femmes étaient porteuses du déficit G6PD ou de l'alpha-thalassémie. Ces données soulignent l'importance de considérer simultanément les différents désordres érythrocytaires existant parmi la population considérée, pour étudier les mécanismes protecteurs conférés par le portage d'HbS contre le paludismeMalaria is a tropical disease resulting from infection by the parasite Plasmodium falciparum transmitted by mosquito bite. The symptoms of malaria are caused by the development of P. falciparum in red blood cells (RBCs). For centuries, malaria has put pressure on the human genome, having selected mutations conferring protection against severe forms of the disease. This is the case of the mutation of the hemoglobin gene (HbA), the principal constituent of RBCs. The mutated form of the gene produces abnormal hemoglobin (HbS). In contrast to sickle cell disease (HbSS), the heterozygous carriage (sickle cell trait) of this mutation (HbAS) is asymptomatic. Healthy HbAS carriers are protected from severe symptoms of malaria. Today, the mechanisms responsible for this protection remain partially understood. During its intra-erythrocytic development, P. falciparum modifies the RBC membrane and cytoskeleton to expose parasite proteins at the surface of the erythrocyte. Among these proteins, the major parasitic adhesin, "P. falciparum erythrocyte membrane protein 1" (PfEMP1), binds to endothelial receptors, resulting in cytoadherence and sequestration of infected RBCs. This cytoadherence permits the infected RBCs to avoid splenic clearance. Studies have shown that infected HbAS RBCs have a reduced cytoadherence, in association with an abnormal PfEMP1 display. This PhD project attempts to decipher the mechanisms of resistance conferred by the sickle cell trait against P. falciparum malaria. The first part of this project considers the phosphoproteome of the infected HbAA and HbAS red cell membranes. Parasitic proteins exposed on the surface of RBCs interact with erythrocyte proteins involved in the anchorage of the cytoskeleton to the erythrocyte membrane. These human proteins belong to the Ankyrin-R and the junctional complexes. The oxidative stress generated by sickle cell trait, and by parasite invasion, disrupts the kinase / phosphatase balance, leading to modulation of protein phosphorylation. As protein interactions could be regulated by their state of phosphorylation, this modulation may interfere in parasite antigens' display. Thus, protein membrane extracts of infected HbAA and HbAS RBCs were produced and analyzed by mass spectrometry and Western-Blot. This study showed that the sickle cell trait modulated the phosphorylation of erythrocyte proteins of the infected RBCs (membrane transporters and cytoskeletal proteins mainly), but also that of parasite proteins. The second part of the project deals with the anti-VAR2CSA antibody response in the context of pregnancy-associated malaria according to the heterozygous carriage of hemoglobin S. Placental malaria is one of the severe forms of malaria, resulting from the cytoadherence of infected RBCs in the placenta. This cytoadherence results from the interaction of a particular PfEMP1, VAR2CSA, with chondroitin sulfate A expressed on syncytiotrophoblasts. 159 plasma samples of HbAA and HbAS Beninese women, collected at delivery, were used to measure their ability to recognize VAR2CSA on the surface of infected HbAA and HbAS RBCs. Immune recognition of infected HbAS RBCs by plasma from HbAS mothers is significantly lower than the immune recognition of infected HbAA RBCs by HbAA mothers' plasma. In addition, other genetic diseases affecting RBCs may influence the antibody response to parasitized red blood cells. Co-carriage of G6PD deficiency and alpha-thalassemia with HbS were assessed for this study group. G6PD deficiency and alpha-thalassemia were present in, respectively, 26.7% and 51.7% of the women. These data underline the importance of simultaneously considering the different erythrocyte disorders present at high prevalence among the population considered, in order to study the protective mechanisms conferred by the carriage of HbS against malaria
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Manirakiza, Alexandre. "Utilisation du test de diagnostic rapide(paracheck-pf®) en consultation prénatale dans le cadre du traitement antipaludique à Bangui, République Centrafricaine." Thesis, Aix-Marseille, 2012. http://www.theses.fr/2012AIXM5040/document.
Full textAbstract:
Entre juin et septembre 2009, nous avons réalisé une étude transversale pour évaluer l'état de la prise en charge du paludisme chez la femme enceinte à Bangui. Les résultats de cette évaluation ont montré que dans les services de consultation prénatale (CPN) de Bangui, 28,8% des femmes enceintes reçoivent à titre curatif au moins une prescription de médicament antipaludique pendant leur grossesse. La quinine et les combinaisons à base d'artémisinine, antipaludiques compatibles avec la grossesse, sont prescrites dans des proportions de 56,7% et 26,8% respectivement. Par contre, la confirmation du paludisme par un examen de laboratoire est réalisée seulement dans 18,9% des cas avant la prescription du traitement. Les deux doses recommandées de traitement préventif intermittent du paludisme par la sulfadoxine-pyrimethamine (TPIsp) sont administrées à 30,5% des femmes pendant leur grossesse. Les moustiquaires imprégnées d'insecticide à longue durée (MIILD) sont utilisées par 42,4% des femmes enceintes. Malgré ce, la prévalence de la parasitémie placentaire à l'accouchement est relativement faible (4%). Ces données nous ont amené à réaliser une étude dont l'objectif était d'évaluer l'intérêt de l'introduction d'un test de diagnostic rapide (TDR) sur la rationalisation du traitement du paludisme chez les femmes enceintes lors des CPN. Entre octobre 2009 et octobre 2011, nous avons réalisé une étude sur une cohorte de 76 femmes enceintes. Le nombre de traitements antipaludiques après confirmation du paludisme par TDR Paracheck-Pf® lors des CPN a été déterminé sur cette cohorteFrom June to September 2009, we designed a cross-sectional study aiming to assess malaria management during pregnancy in antenatal health care in Bangui. Our findings showed that antimalarials are prescribed to 28.8% of pregnant women attending antenatal clinics (ANCs) in Bangui. Quinine and artemisinin combined therapies are widely used (56.7% and 26.8% respectively). However, laboratory diagnosis of malaria infection is performed for solely 18.9% of consultants. The recommended two doses of intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTsp) are given to 30.5% of pregnant women, while 42.4% of them use the insecticides treated nets (ITNs). Nonetheless, the prevalence of placental malaria at delivery is relatively low (4%). From those preliminary data of our study we assessed the impact of a systematic rapid diagnosis test (RDT) of malaria during pregnancy on antimalarials prescription, during the period from October 2009 and October 2011. The proportions of antimalarial treatment episodes were compared in two groups of women: a cohort of 76 pregnant women presenting at their ANCs visits, in which a systematic screening of malaria with the RDT Paracheck-Pf® was performed and a control group of women who delivered in the same period. Our findings showed that in the cohort, there was a proportion of 13.8 % of positive RDT, hence requiring antimalarial treatment, while the proportion of antimalarials prescriptions in the control group was 26.3% (P = 0.0001). The avoidable rate of unnecessary antimalarials prescriptions was estimated at 47%
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Hliscs, Marion. "Functional Characterization of Actin Sequestering Proteins in Plasmodium berghei." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2012. http://dx.doi.org/10.18452/16452.
Full textAbstract:
Plasmodien spp. sind obligat intrazellulär lebende Parasiten, welche einen evolutionär konservierten aktinabhängigen molekularen Motor für die Fortbewegung und den Wirtszellein- und -austritt nutzen. In dieser Arbeit werden die Aktinregulatoren Adenylyl- Zyklase- assoziierte Protein (C-CAP), Profilin sowie die Aktin depolymerizierenden Faktoren 1 und 2 (ADF1, ADF2) in Plasmodium berghei charakterisiert. Die Geninaktivierung von C-CAP besitzt keinen Einfluss auf die Entwicklung von pathogenen Blutstadien. C-cap(-) Ookineten bewegen sich jedoch deutlich langsamer, sind aber in der Lage den invertebraten Wirt zu infizieren. Defekte treten während der extrazellulären Replikationsphase im Mosquito auf und führen zu Abbruch des Lebenszykluses. Die erfolgreiche Komplementierung der Defekte mit dem orthologen Gen aus Cryptosporidium parvum CpC-CAP bestätigt die funktionale Redundanz zwischen beiden Proteinen. Profilin, als ein weiteres G-Aktin bindendes Protein, ist hingegen nicht in der Lage die Defekte des c-cap(-) Parasiten auszugleichen. Mittels transgener Parasiten welche ein C-CAPmCherry Fusionsprotein exprimieren, wird das C-CAP Protein im Zytoplasma lokalisiert. Erstmals wird mit dieser Arbeit ein G-Aktin bindendes Protein, C-CAP beschrieben, welches eine essentielle Funktion während der Oozystenreifung in Plasmodium berghei besitzt. Die Transkription der Aktinregulatoren Profilin, ADF1 und ADF2 wird in Sporozoiten drastisch herunterreguliert und Profilin kann als Protein nicht mehr nachgewiesen werden. Um die Funktion von C-CAP und Profilin zu überprüfen, wurden beide Proteine spezifisch in Sporozoiten überexprimiert. Diese Parasiten sind nicht in der Lage die Speicheldrüsen des Wirtes zu besiedeln, was zum Abbruch des Lebenszykluses führt. Anhand dieser Ergebnisse entwickele ich ein „minimalistisches“ Model zur Beschreibung der Aktinregulation in Sporozoiten in welchem das ADF1 als regulatorisches Protein im Mittelpunkt steht.Plasmodium spp. are obligate intracellular parasites, which employ an conserved actin-dependent molecular motor machinery that facilitates their motility, host cell invasion and egress. In this work I report implications of the actin-regulators adenylyl cyclase-associated protein (C-CAP), profilin and actin depolymerization factor 1 and 2 (ADF1, ADF2) in distinct and previously unanticipated cellular processes during the life cycle of in the rodent malarial parasite Plasmodium berghei. Fluorescent tagging of the endogenous C-CAP genetic locus with mCherry revealed cytosolic distribution of the protein. Gene deletion demonstrates that the G-actin binding protein C-CAP is entirely dispensable for the pathogenic blood stages. Ookinetes show reduced motility, but are competent infecting the mosquito host. Defects emerging in the extracellular replication phase, leading to attenuation of oocyst maturation. Successful trans-species complementation with the C. parvum C-CAP ortholog, rescues the c-cap(-) phenotype and proves functional redundancy. The actin regulator profilin fails to rescue the defects of c-cap(-) parasites, despite sharing its actin sequestering activity with C-CAP. Taken together, C-CAP is the first G-actin sequestering protein of Plasmodium species that is not required for motility but performs essential functions during oocyst maturation. Characterization of the actin regulators profilin, ADF1 and ADF2 revealed dramatic transcriptional down-regulation and the absence of the profilin protein in sporozoites. To test whether G-actin binding proteins interfere with sporozoite functions, I ectopically overexpressed of profilin and C-CAP stage-specifically in sporozoites. This conducted to abolishment of salivary gland invasion and lifecycle arrest. Based on these unexpected findings and the available literature data, I developed a “minimalistic model” for actin regulation in sporozoites that predicts ADF1 as the main actin-turnover regulating factor.
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"Emerging Drug Resistance of Plasmodium sp Associate with Misdiagnosis of Malaria." Tulane University, 2014.
Find full text
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Dennis, Adelaide Sandra Mild. "PfATP4 and the biochemical signature of PfATP4-associated compounds." Phd thesis, 2018. http://hdl.handle.net/1885/149540.
Full textAbstract:
In 2016 more than 200 million cases of malaria were reported and
nearly 500 000 people died from the disease. Although there are
antimalarial drugs available, the most virulent species of the
disease-causing parasite, Plasmodium falciparum, has evolved some
level of resistance to many of them. A global effort to
accelerate antimalarial drug discovery has led to the finding
that one particular parasite protein, the P-type ATPase PfATP4,
appears to be the target of a number of potent novel antimalarial
compounds. Two of these ‘PfATP4-associated compounds’ have
entered the clinical pipeline; one of these is the spiroindolone
KAE609 (also known as cipargamin).
PfATP4 is located on the plasma membrane of the parasite.
Although an early study yielded evidence consistent with PfATP4
being a Ca2+ transporter, more recent studies have provided
evidence that PfATP4 extrudes Na+ ions from the parasite while
importing H+ ions, allowing the parasite to maintain a large
inward Na+ concentration gradient. When parasites are exposed to
PfATP4-associated compounds, there is an increase in the Na+
concentration and the pH inside the parasite.
In the work reported in this Thesis I have investigated the
nature and function of PfATP4, extended the characterisation of
the effects of PfATP4-associated compounds on mature
asexual-stage P. falciparum parasites, and identified a number of
new compounds of this class.
A phylogenetic analysis revealed that PfATP4 belongs to a unique
subgroup of Type II P-type ATPases, specific to apicomplexan
parasites and their closest relatives.
Previous studies have reported that PfATP4-associated compounds
cause parasite swelling. The effect of KAE609 on the volume of
isolated parasites and parasitised erythrocytes was characterised
using a Coulter Multisizer. KAE609 caused isolated parasites to
swell in a Na+-dependent manner. KAE609 also caused intact
infected erythrocytes to swell and thereby increase in osmotic
fragility. Another six PfATP4-associated compounds were also
shown to induce parasite swelling. Protecting parasitised
erythrocytes from excessive swelling by growing them in a
hyperosmotic medium increased the concentration of KAE609 that
was required to kill the parasite, consistent with cell swelling
playing a role in the mechanism of action of KAE609.
The ‘biochemical signature’ of PfATP4-associated compounds
was used to identify novel PfATP4-associated compounds from a set
of 400 diverse drug-like compounds. Experiments investigating the
effects of these compounds on parasite Na+, pH and volume, as
well as cross-resistance studies using KAE609-resistant
parasites, provided evidence that eleven compounds act in a
manner consistent with inhibition of PfATP4. These compounds add
to the chemical diversity of known PfATP4-associated compounds.
PfATP4 has previously been proposed to be a Ca2+ transporter.
The role of Ca2+ in the mechanism of action of PfATP4-associated
compounds was explored using a physiological approach. The
results support the prevailing view that PfATP4-associated
compounds disrupt Na+ homeostasis directly, and are inconsistent
with a role for Ca2+ in this phenomenon.
This study furthers our understanding of the effects of
PfATP4-associated compounds on parasite physiology and, in
extending our knowledge of the characteristic biochemical
signature of these compounds, provides a basis for identifying
further such compounds.
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Nkoka, Owen, and Owen Nkoka. "Assessment of factors associated with use of malaria interventions among Malawian women." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/k6f793.
Full text
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Stradi, Melanie. "Genetic and biochemical characterization of the cytochrome P450, CYP6P9, associated with pyrethroid resistance in the African malaria vector Anopheles funestus." Thesis, 2012. http://hdl.handle.net/10539/11083.
Full textAbstract:
Anopheles funestus Giles is a major vector of malaria in Africa and pyrethroid resistance observed in this species has disrupted malaria control in southern Africa. Metabolic detoxification, based on the overproduction of cytochrome P450s, specifically CYP6P9 and CYP6P13, was identified as the principal resistance mechanism in both field and laboratory populations. This project aimed to characterize this resistance mechanism further, both on a molecular as well as a biochemical level. Biochemical analysis on total P450 activity levels revealed a 25.5-fold increase in the resistant strain compared to a pyrethroid susceptible strain. Analysis of the effect of pyrethroids on mRNA expression of three P450 genes showed that two of them (CYP6P9 and CYP6P13) as well as Cytochrome oxidase I (COI) was induced. HPLC analysis using a heterologously (recombinant) expressed CYP6P9 enzyme, showed that CYP6P9 was able to metabolize the pyrethroid permethrin and that it was catalytically efficient. Immunoblotting revealed no significant variation in CYP6P9 protein abundance between the different An. funestus colonies. Although an approximate molecular weight (≈Mr) of 58kDa was predicted for CYP6P9, two fragments were detected at ≈Mr 52,000 and ≈45,000. The smaller fragment was very likely a result of proteolytic degradation. Statistical analysis revealed there was no significant difference in CYP6P9 protein expression between strains or sexes. Although CYP6P9 mRNA is over-expressed it is important to assess the abundance of protein as well when elucidating whether a gene and its protein are important candidates in resistance. Differences in pyrethroid resistant or susceptible profiles of An. funestus colonies could be related to enzyme affinity for substrate and stability of CYP6P9 protein however; it is recommended that further studies need to be done before any conclusions can be drawn. CYP6P9 in An. funestus is a major candidate in conferring pyrethroid resistance and the pyrethroid resistant strain is able to metabolize the pyrethroid permethrin.
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Obala, Andrew Ambogo. "Malaria vector populations associated with the agricultural development at Mamfene, Northern KwaZulu-Natal, South Africa." Thesis, 1995. http://hdl.handle.net/10413/10331.
Full textAbstract:
The irrigation farming methods on the Makhathini Flats are thought to be
responsible for recent increase in malaria cases in the Mamfene area of
northern KwaZulu-Natal despite ongoing malaria control activities. Their
coincidence with the period of intensive fanning is an interesting one. This
study was therefore carried out to determine the relationship between larval
habitats and adult mosquito population in malaria transmission using
Geographic Information System (GIS).
Four types of breeding sites were utilised by malaria vectors in Mamfene, viz;
types 1, II, III and IV. Habitat type I was tap pools, type II was irrigation
spillage in agricultural land, type III was spillage outside but adjacent to the
agricultural land and type IV was depression pools located both in the
Balamhlanga swamp and inland. The cumulative larval density in all habitats
peaked in March 1995 (20/man-hr), with irrigation spillage (type III) recording
the highest density index (33/man-hr) as compared to tap pools (type I) which
recorded 32.8/man-hr while other waterbodies recorded I3 .4/man-hr (type II)
and O.5/man-hr (type IV) respectively. Subsamples of both larvae and adults of An. gambiae group were identified by
the Polymerase Chain Reaction (PCR) technique. Of the larvae identified,
94.1 % and 5.9% (n=289) were An. arabiensis and An. quadriannulatus
respectively while in the adult component, the composition was 98.7% and
1.3% (n=303) for An. arabiensis and An. quadriannulatus respectively. This
confirmed An. arabiensis as the dominant malaria vector in Mamfene area
while the exophilic behaviour of An. quadriannulatus was portrayed. Of the
An. gambiae group dissected for parity, 51 .5%) were found parous. This is an
indication that the population was old and was able to maintain transmission
locally despite ongoing vector control measures.
The Global Positioning System (GPS) was used to position larval and adult
mosquito sampling sites. The spatial distribution of adult mosquitoes from the
breeding sites were plotted using GIS soft ware (Map Info ) and the distance
between the breeding sites and study houses were measured using a utility
distance tool. With the aid of GIS, the adult mosquito density in houses could
be used as an indicator to locate the breeding sites in the vicinity. The
importance of these findings in terms of application in cost-effective malaria
control cannot be over-emphasized.Thesis (M.Sc.)-University of Natal, Pietermaritzburg, 1995.
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Mbago, Thomas. "Factors associated with utilization of insecticide treated nets among pregnant women in northern regions of Namibia." Thesis, 2014. http://hdl.handle.net/10539/15422.
Full textAbstract:
A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Science in Epidemiology and BiostatisticsBackground: Malaria causes an overwhelmingly large number of cases and deaths around the globe every year, with over 90% of deaths occurring in sub-Saharan Africa. Namibia is among the sub Saharan countries that have malaria as a major public health problem, affecting most pregnant women and children in the northern regions. Insecticide treated net (ITN) distribution has been expanded in the northern regions since 2005, yet there is low ITN utilization. The associated factors for low ITN utilization are not well established. Objective: This study aimed to determine factors affecting the utilization of ITN among pregnant women in northern regions of Namibia. Specific objectives were to: (1) describe coverage of ITNs among pregnant women in terms of possession; (2) describe the utilization rate of ITN among pregnant women in northern regions; and (3) determine the association between various factors and utilization of ITN among pregnant women. The first study outcome measure was utilization of ITN, defined as an individual pregnant woman who had used an ITN the night before the survey day. The second outcome measure was coverage of ITNs, defined as possession of at least one ITN in each household, irrespective of whether or not it was being used. Methods: A cross sectional study design was used, using secondary data from a nationally representative survey which collected data on malaria interventions in regions of Namibia. The original survey collected data from a representative sample of 3000 households from 120 primary sampling units (PSUs) in nine regions country wide, using a stratified sampling method of two stages. This study targeted pregnant women in four northern regions, namely; Kavango, Ohangwena, Oshana and Omusati, in both rural and urban areas; who participated in the 2009 Namibia Malaria Indicator Survey (NMIS) from 4 April to 10 June 2009. A total of 83 pregnant women were included in the analysis out of 194 pregnant women who were interviewed during the 2009 survey. In the descriptive analyses, we described the demographic characteristics of pregnant women. In the analytic analyses, univariable and multivariable analysis (logistic regression) were conducted. Logistic regression was used to determine risk factors associated with ITN utilization. Results: The utilization of ITN was high (47%) for young women aged 15-24 years old. Overall, 67% of pregnant women aged 15-44 years old slept under bed nets the night prior the survey day. In the univariable analyses, being 35-44 years of age (OR 0.25; 95% CI: 0.07-0.89, p<0.02) and having information about malaria (OR 0.28, 95% CI: 0.09-0.85, p<0.03), were independently associated with ITN utilization. In the multivariate logistic regression model, none of the explanatory variables were significant at the 5% level. The study showed 98.8% overall coverage of ITNs among pregnant women in terms of possession. Conclusion: These findings have implications for malaria interventions in Namibia. While almost all the pregnant women recruited in the study possessed ITNs, a significant proportion did not utilize them. Older women were more likely to utilize ITNs. Interventions to improve utilization among pregnant women should target younger women below the age of 35. Women that had information on malaria were more likely to utilize ITN. Sensitising women about the epidemiology of malaria across Namibia could lead to improved utilization of ITNs. A national malaria strategic plan needs to incorporate targeted reproductive women’s education for malaria control in Namibia.
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Chalwe, Victor F. "Factors associated with mortality from childhood malaria in Navrongo DSS Site, Ghana, 1995-2000." Thesis, 2008. http://hdl.handle.net/10539/4821.
Full textAbstract:
ABSTRACT: Background: Malaria is endemic throughout Ghana and continues to be a major public
health concern especially among pregnant women and children under the age of five. The
Ministry of Health (MoH) estimates that over the past ten years, there have been 2-3
million cases of malaria each year, representing 40 percent of outpatient cases, while
severe malaria accounts for 33-36 percent of in-patients. Malaria also accounts for 25
percent of the deaths in children under the age of five (GHS, 2001).
Correct identification of risk factors could focus interventions at reducing malaria
mortality in children. Demographic Surveillance System (DSS) sites have been
established and they generate high quality population based longitudinal health and
demographic data. The DSS conduct Verbal Autopsies to determine probable causes of
death.
Objective: This study examines factors affecting childhood malaria mortality in Northern
Ghana, using longitudinal data collected by the Navrongo DSS during the period 1995-
2000. It deals especially with the role of socioeconomic factors (mother’s education,
family wealth index based on the possessions and housing characteristics and residence, and possession of bed net) and the demographic characteristics (child’s sex and age, and
mother’s age).
Design: Secondary data analysis of longitudinal data collected by the Navrongo Health
Research Centre. Multinomial logistic regression was used to compare the relative risk in
three groups of children i.e. those who died of Malaria and those who died of other
causes to those who survived as base. Results: Overall, for the deaths due to malaria, older children (1-5years) had a higher risk
(RRR 1.4, 95%CI 1.25-1.57 P <0.0001) of dying compared to the infants. Equally,
children born of older mothers (maternal age at birth of child >30 years) had a higher risk
(RRR 1.28, 95%CI 1.15-1.42 P <0.0001).
However, maternal education and residence had a protective effect, with children born of
mothers who had some education (RRR 0.79, 95%CI 0.67-0.93 P=0.004) and residing in
urban area (RRR 0.61, 95%CI 0.46-0.82 P=0.001) having a lower risk. Similarly, those
children whose families are in the highest wealth index had a lower risk (RRR 0.76,
95%CI 0.63-0.91 P=0.003).
Interestingly, the same factors were associated with deaths occurring due to other causes,
but with varying degree of association. Whereas sex of child was not associated with
malaria deaths, being female offered a lower risk of dying from other causes (RRR 0.9, 95%CI 0.84-0.98 P=0.017). It was observed that children in the older age group (1-5
years) were at higher risk of dying (RRR 1.14, 95%CI 1.05-1.25 P=0.002) just as those
born of older mothers (RRR 1.16, 95%CI 1.07-1.26 P <0.0001). Even in this group, maternal education (RRR 0.87, 95%CI 0.76-0.98 P=0.023), a higher wealth index (RR
0.87, 95%CI 0.77-0.99 P=0.032 and RRR 0.63 95%CI 0.54-0.73 P <0.0001 for the two
highest categories of wealth indices respectively), and area of residence (RRR 0.67,
95%CI 0.55-0.83 P <0.0001) offered a reduction in the risk of dying.
Conclusion: The study identified the risk factors (age and sex of the child and mother’s
age, maternal education, wealth and residence of the family) associated with malaria
mortality and other causes of death in childhood in northern Ghana and this should help
formulate cost effective interventions such as health education.
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Duarte, Lurdes da Glória Rodrigues. "Unraveling maternal and fetal genetic factors protecting from Pregnancy Associated Malaria in the mouse." Doctoral thesis, 2013. http://hdl.handle.net/10362/14237.
Full textAbstract:
Malaria is one of the most devastating diseases in the world. In Plasmodium endemic regions, pregnant women are among the most vulnerable groups. Pregnancy Associated Malaria (PAM) threatens both maternal and foetal lives. Despite differences between human and mouse placentas PAM mouse models recapitulate key pathological features of human PAM. Here we describe new PAM models of mid gestation infection in the C57BL/6 mouse.(...)
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Dadi, Berhanu Berga. "Modeling malaria cases associated with environmental risk factors in Ethiopia using geographically weighted regression." Master's thesis, 2020. http://hdl.handle.net/10362/95138.
Full textAbstract:
Dissertation submitted in partial fulfilment of the requirements for the degree of Master of Science in Geospatial TechnologiesIn Ethiopia, still, malaria is killing and affecting a lot of people of any age group somewhere in the country at any time. However, due to limited research, little is known about the spatial patterns and correlated risk factors on the wards scale. In this research, we explored spatial patterns and evaluated related potential environmental risk factors in the distribution of malaria cases in Ethiopia in 2015 and 2016. Hot Spot Analysis (Getis-Ord Gi* statistic) was used to assess the clustering patterns of the disease. The ordinary least square (OLS), geographically weighted regression (GWR), and semiparametric geographically weighted regression (s-GWR) models were compared to describe the spatial association of potential environmental risk factors with malaria cases. Our results revealed a heterogeneous and highly clustered distribution of malaria cases in Ethiopia during the study period. The s-GWR model best explained the spatial correlation of potential risk factors with malaria cases and was used to produce predictive maps. The GWR model revealed that the relationship between malaria cases and elevation, temperature, precipitation, relative humidity, and normalized difference vegetation index (NDVI) varied significantly among the wards. During the study period, the s-GWR model provided a similar conclusion, except in the case of NDVI in 2015, and elevation and temperature in 2016, which were found to have a global relationship with malaria cases. Hence, precipitation and relative humidity exhibited a varying relationship with malaria cases among the wards in both years. This finding could be used in the formulation and execution of evidence-based malaria control and management program to allocate scare resources locally at the wards level. Moreover, these study results provide a scientific basis for malaria researchers in the country.
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De, Ridder Jaco. "In Silico analysis of malaria parasite databanks for specific genes and motifs associated with immune evasion." Diss., 2001. http://hdl.handle.net/2263/27675.
Full textAbstract:
In Silica analysis of available biological data is a powerful tool for not only the identification of new genes, but also to study evolutionary relationships and regulatory mechanisms. In this study, a number of bioinformatic tools and techniques were applied on the available sequence data of the malaria parasite, Plasmodium falciparum. In Silica techniques were used for the identification of a genomic sequence tag (GST) matching the facilitated glucose transporter family as assessed by BLAST. The open reading frame encoding the fUll-length glucose transporter gene was subsequently assembled from contig sequences of chromosome 2 of the malaria parasite. The frequency of occurrence of di-, tri- and tetranucleotide sequences in both the coding and non-coding regions of chromosome 2 of P. falciparum was also exhaustively analysed. The relative abundance (observed, compared to expected values) of these oligonucleotide sequences, normalised for the nucleotide base composition, was calculated as an odds ratio and compared to those of other organisms. These relative abundancies are referred to as the organism's genomic signature. The CC•GG and CG-dinucleotides exhibited the highest and the lowest odds ratios, respectively. These genome signatures were shown to be constrained by the codon preference and amino acid abundancies. A number of genes with genomic signatures differing significantly from the average signature were also identified and were deduced to be acquired by lateral transfer from unidentified sources. A definite association between interspaced TGCA tetranucleotides and polymorphic traits of the FC27 allele of merozoite surface antigen 2 (MSA-2) was shown. The observed switching and deletion of a limited number of identical nucleotide sequences of several alleles interspersed between direct repeats, provided clues to potential mechanisms employed by the parasite to affect antigenic polymorphism. The identification of a number of motifs for intragenic (homologous) recombination led us to propose a mechanism by which the parasite achieves antigenic variation in single copy genes. These results have profound implications for the design of candidate anti-malarial vaccines, microsatellite typing and characterisation of proteins mediating these recombination events.Dissertation (MSc (Biochemistry))--University of Pretoria, 2006.
Biochemistry
unrestricted
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Kern, Selina Melanie. "Functional characterization of splicing-associated kinases in the blood stages of the malaria parasite Plasmodium falciparum." Doctoral thesis, 2014. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-115219.
Full textAbstract:
Besides HIV and tuberculosis, malaria still is one of the most devastating infectious diseases especially in developing countries, with Plasmodium falciparum being responsible for the frequently lethal form of malaria tropica. It is a major cause of mortality as well as morbidity, whereby pregnant women and children under the age of five years are most severely affected. Rapidly emerging drug resistances and the lack of an effective and safe vaccine hamper the combat against malaria by chemical and pharmacological regimens, and moreover the poor socio-economic and healthcare conditions in malaria-endemic countries are compromising the extermination of this deadly tropical disease to a large extent. Malaria research is still questing for druggable targets in the parasitic protozoan which pledge to be refractory against evolving resistance-mediating mutations and yet constitute affordable and compliant antimalarial chemotherapeutics. The parasite kinome consists of members that represent most eukaryotic protein kinase groups, but also contains several groups that can not be assigned to conservative ePK groups. Moreover, given the remarkable divergence of plasmodial kinases in respect to the human host kinome and the fact that several plasmodial kinases have been identified that are essential for the intraerythrocytic developmental cycle, these parasite enzymes represent auspicious targets for antimalarial regimens. Despite elaborate investigations on several other ePK groups, merely scant research has been conducted regarding the four identified members of the cyclin-dependent kinase-like kinase (CLK) family, PfCLK-1-4. In other eukaryotes, CLKs are involved in mRNA processing and splicing by means of phosphorylation of serine/arginine-rich (SR) proteins, which are crucial components of the splicing machinery in the alternative splicing pathway. All four PfCLKs are abundantly expressed in asexual parasites and gametocytes, and stage-specific expression profiles of PfCLK-1 and PfCLK-2 exhibited nucleus-associated localization and an association with phosphorylation activity. In the course of this study, PfCLK-3 and PfCLK-4 were functionally characterized by indirect immunofluorescence, Western blot analysis and kinase activity assays. These data confirm that the two kinases are primarily expressed in the nucleus of trophozoites and both kinases possess in vitro phosphorylation activity on physiological substrates. Likewise PfCLK-1 and PfCLK-2, reverse genetic studies exhibited the indispensability of both PfCLKs on the asexual life cycle of P. falciparum, rendering them as potential candidates for antiplasmodial strategies. Moreover, this study was conducted to identify putative SR proteins as substrates of all four PfCLKs. Previous alignments revealed a significant homology of the parasite CLKs to yeast SR protein kinase Sky1p. Kinase activity assays showed in vitro phosphorylation of the yeast Sky1p substrate and SR protein Npl3p by precipitated PfCLKs. In addition, four homologous plasmodial SR proteins were identified that are phosphorylated by PfCLKs in vitro: PfASF-1, PFSRSF12, PfSFRS4 and PfSR-1. All four parasite SR splicing factors are predominantly expressed in the nuclei of trophozoites. For PfCLK-1, a co-localization with the SR proteins was verified. Finally, a library of human and microbial CLK inhibitors and the antiseptic chlorhexidine (CHX) was screened to determine their inhibitory effect on different parasite life cycle stages and on the PfCLKs specifically. Five inhibitors out of 63 compounds from the investigated library were selected that show a moderate inhibition on asexual life cycle stages with IC50 values ranging between approximately 4 and 8 µM. Noteworthy, these inhibitors belong to the substance classes of aminopyrimidines or oxo-β-carbolines. Actually, the antibiotic compound CHX demonstrated an IC50 in the low nanomolar range. Stage-of-inhibition assays revealed that CHX severely affects the formation of schizonts. All of the selected CLKs inhibitors also affect gametocytogenesis as well as gametogenesis, as scrutinized in gametocyte toxicity assays and exflagellation assays, respectively. Kinase activity assays confirm a specific inhibition of CLK-mediated phosphorylation of all four kinases, when the CLK inhibitors are applied on immunoprecipitated PfCLKs. These findings on PfCLK-inhibiting compounds are initial attempts to determine putative antimalarial compounds targeting the PfCLKs. Moreover, these results provide an effective means to generate chemical kinase KOs in order to phenotypically study the role of the PfCLKs especially in splicing events and mRNA metabolism. This approach of functionally characterizing the CLKs in P. falciparum is of particular interest since the malarial spliceosome is still poorly understood and will gain further insight into the parasite splicing machineryNeben HIV und Tuberkulose stellt Malaria vor allem in Entwicklungsländern immer noch eine der verheerendsten Infektionskrankheiten dar, wobei Plasmodium falciparum für die oft tödlich verlaufende Form der Malaria tropica verantwortlich ist. Sie ist eine der Hauptgründe für Mortalität und Morbitität, von der vor allem schwangere Frauen und Kinder unter fünf Jahren am schlimmsten betroffen sind. Das Fehlen eines effektiven und ungefährlichen Impfstoffes und sich schnell ausbreitende Medikamentenresistenzen erschweren die Bekämpfung von Malaria mit Arzneimitteln. Darüber hinaus beeinträchtigen die schlechten sozioökonomischen Bedingungen und der mangelhafte Zustand des Gesundheitssystems in Malaria-endemischen Ländern die Elimination dieser tödlichen Tropenkrankheit in hohem Maße. Die Malariaforschung ist immer noch auf der Suche nach vielversprechenden Angriffspunkten im Parasiten, die widerstandsfähig gegenüber sich entwickelnden resistenz-vermittelnden Mutationen sind und dennoch erschwingliche und verträgliche Chemotherapeutika gegen Malaria darstellen. Das Kinom des Parasiten besteht aus Vertretern der meisten eukaryotischen Proteinkinase-Gruppen und enthält zudem einige Gruppen, die keiner der konventionellen Gruppen zuordenbar sind. Darüber hinaus stellen Kinasen vielversprechende Angriffspunkte für Malariamedikamente dar, da das Parasitenkinom bemerkenswerte Divergenzen gegenüber dem Wirtskinom aufweist und zudem einige Parasitenkinasen identifiziert wurden, die unerlässlich für den Replikationszyklus von asexuellen Parasiten sind. Trotz umfangreicher Untersuchungen anderer Kinasegruppen des Parasiten wurden die vier identifizierten Vertreter der Zyklin-abhängige-Kinase-ähnlichen Kinasen (cyclin-dependent kinase-like kinases, CLKs) bisher kaum untersucht. In anderen Eukaryoten sind CLKs an der mRNA-Prozessierung und am Spleißen durch die Phosphorylierung von Serin/Arginin-reichen (SR-) Proteinen beteiligt, welche wiederum Komponenten der Spleißmaschinerie sind. Alle vier PfCLKs sind abundant exprimiert in asexuellen Parasiten sowie Gametozyten, und stadien-spezifische Expressionsprofile von PfCLK-1 und PfCLK-2 zeigten eine Kern-assoziierte Expression sowie Phosphorylierungsaktivität in in vitro-Aktivitätsstudien. Im Verlauf dieser Studie wurden PfCLK-3 und PfCLK-4 mittels indirekter Immunfluoreszenzstudien, Western Blot-Analysen und Kinaseaktivitätsassays funktionell charakterisiert. Die Ergebnisse bestätigen, dass beide Kinasen vorrangig im Nukleus von P. falciparum-Trophozoiten lokalisiert sind und Phosphorylierungsaktivität gegenüber physiologischen Substraten in vitro aufweisen. Ähnlich wie für PfCLK-1 und PfCLK-2 konnte in Reverse-Genetik-Studien gezeigt werden, dass sowohl PfCLK-3 als auch PfCLK-4 essentiell für den asexuellen Replikationszyklus von P. falciparum sind. Dieser Umstand macht beide Kinasen zu potenziellen Angriffspunkten für antiplasmodiale Bekämpfungsstrategien. Des Weiteren wurde diese Studie ausgeführt, um mögliche Interaktionspartner aller vier PfCLKs zu identifizieren. Vorangegangene Sequenzabgleiche brachten eine bemerkenswerte Homologie der Parasiten-CLKs zur SR-Proteinkinase Sky1p der Bäckerhefe zu Tage. Kinaseaktivitätsassays zeigten Phosphorylierung des Sky1p-Substrates und SR-Proteins Npl3p durch präzipitierte PfCLKs in vitro. Außerdem wurden vier homologe plasmodiale SR-Proteine bzw. mutmaßliche Spleißfaktoren identifiziert, die ebenso von den PfCLKs in vitro phosphoryliert werden: PfASF-1, PFSRSF12, PfSFRS4 und PfSR-1. Alle vier Parasiten-Spleißfaktoren sind vorwiegend in Kernen von Trophozoiten exprimiert. Für PfCLK-1 konnte eine Ko-Lokalisation mit den SR-Proteinen nachgewiesen werden. Abschließend wurden eine Sammlung humaner und mikrobieller CLK-Inhibitoren sowie das Antiseptikum Chlorhexidin (CHX) auf ihren hemmenden Effekt auf verschiedene Lebenszyklusstadien von P. falciparum und gezielt auf die PfCLKs überprüft. Es wurden fünf Inhibitoren aus einer Sammlung von 63 Substanzen auserwählt, die eine moderate Hemmung auf asexuelle Lebenszyklusstadien aufwiesen, mit IC50-Werten zwischen ungefähr 4 und 8 µM. Das Antibiotikum CHX zeigte sogar einen IC50-Wert im niedrigen nanomolaren Bereich. Nachfolgende Stage-of-Inhibition-Assays deckten auf, dass CHX die Entwicklung von Schizonten enorm beeinträchtigt. Wie in Gametozyten-Toxizitätsassays und Exflagellationsassays ermittelt wurde, hemmen alle ausgewählten CLK-Inhibitoren ferner sowohl die Gametozytogenese als auch die Gametogenese. Kinaseaktivitätsassays bestätigen eine spezifische Hemmung der CLK-vermittelten Phosphorylierung aller vier Kinasen, wenn die CLK-Inhibitoren auf immunopräzipitierte PfCLKs angewendet wurden. Diese Erkenntnisse über PfCLK-hemmende Substanzen sind erste Ansätze, um mögliche Wirkstoffe gegen Malaria zu finden, die die PfCLKs als Angriffspunkte haben. Zudem stellen diese Resultate ein wirksames Mittel zur Verfügung, um chemische Kinase-Knockout-Parasiten zu generieren. Diese können dann verwendet werden, um die Rolle der PfCLKs vor allen in Bezug auf Spleißvorgänge und mRNA-Metabolismus phänotypisch zu untersuchen. Der Ansatz, die CLKs des Parasiten funktionell zu charakterisieren, ist von besonderem Interesse, da das Spleißosom des Malariaparasiten immer noch nicht ausreichend erforscht ist. Dadurch können weitere Erkenntnisse über die Spleißmaschinerie des Parasiten gewonnen werden
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